Extracorporeal therapeutic ultrasound for promoting angiogenesis

ABSTRACT

Systems and methods can include wearable, non-invasive ultrasound modalities for treating a variety of medical conditions, including but not limited to peripheral vascular disease. The modality could be therapeutic ultrasound (TUS), and be configured to promote angiogenesis within a patient via stimulation of cavitation and shear stress, among other mechanisms.

This application is a continuation of U.S. Application No. 16/282,237,filed Feb. 21, 2019, which is a continuation of PCT Application No.PCT/US2017/056800, filed on Oct. 16, 2017, which claims the benefitunder 35 U.S.C. § 119(e) as a nonprovisional application of U.S. Prov.App. No. 62/408,783 filed on Oct. 16, 2016, which is incorporated byreference in its entirety.

BACKGROUND

Peripheral arterial disease (PAD) is a highly prevalent condition,affecting approximately 202 million people worldwide and 8.5 millionpeople in the USA. Of these, approximately one-third are symptomaticwith claudication (lower extremity muscle pain with walking that limitsactivity), and 2-3% progress to critical limb ischemia (CLI), which is ahighly morbid condition associated with resting pain, skin ulcers, andgangrene, often requiring amputation.

Current treatments for PAD have demonstrated limited efficacy. Patientswith asymptomatic PAD can be treated with anti-platelet medications(e.g., aspirin, clopidogrel) and cholesterol-lowering medications suchas statins in an attempt to reduce lower extremity atheroscleroticburden and to treat concomitant coronary artery disease (CAD). However,approximately 75% progress to develop symptoms of claudication or CLI.Patients with claudication have been shown to benefit from supervisedexercised therapy and the medication cilostazol, however approximately30% progress with worsening claudication, or to develop CLI.Revascularization with bypass surgery, angioplasty or stent implantationis recommended for refractory claudication or CLI, but is associatedwith 20-40% rates of restenosis.

Recently, acoustic energy modalities such as shock wave therapy (SWT)and therapeutic ultrasound (TUS; also referred to in prior literature ashigh-intensity focused ultrasound (HIFU) or low-intensity pulsedultrasound (LIPUS)) have been shown to promote angiogenesis and improveperfusion in CAD. SWT is currently clinically approved in Europe andJapan for the treatment of refractory angina, but not PAD. The abovetreatments currently require intermittent treatments, such as for 20minutes approximately three times a week with devices that requirepositioning and application by a healthcare provider. This potentiallysignificantly limits clinical use as it can be time-intensive for healthcare providers, and also may merely provide temporary increases in bloodflow via vasodilation. While approved/marketed and non-invasive TUSdevices do currently exist, to the inventors’ knowledge, none aredesigned for the human lower extremity, including the calf in somecases, and their acoustic amplitudes, frequencies, and fields areinsufficient to generate the vascular bioeffects necessary forreperfusion of PAD patients. As such, more efficacious systems andmethods are needed, including wearable systems that can be comfortablyworn at home by patients for extended durations and provide relativelylong-term clinical benefits such as increased blood flow and symptomaticrelief.

SUMMARY

Systems and methods as disclosed herein can offer in some embodiments anon-invasive, non-surgical, outpatient treatment for peripheral vasculardisease (PVD), including PAD and a variety of other indications, whichcan be used throughout the lifespan of the patient to treat symptoms andprevent disease recurrence. Some embodiments can advantageously reducethe incidence of amputations, hospitalizations and other complicationsof advanced PAD, adding substantial value for patients, physicians,providers, and payers alike. Some embodiments can also be used as anadjunctive treatment to invasive procedures, augmenting the capacity ofthe limited number of physicians trained in endovascular techniques.

Systems and methods can include wearable, non-invasive ultrasoundmodalities for treating a variety of medical conditions. Theseconditions include but are not limited to peripheral vascular disease(including PAD), and venous disease such as venous insufficiency.Conventional TUS devices used for physical therapy, CAD, and othermedical indications are configured with the sole, supposed goal ofpromoting vasodilation and increased blood flow, although evidence forincreased blood flow and the mechanisms of these effects have so far notyet been described. In contrast, in some embodiments, systems andmethods as disclosed herein can advantageously promote not onlyvasodilation, but also unexpectedly long-term angiogenesis andcollateralogenesis through one, two, or more ultrasound-mediatedmechanisms. Not to be limited by theory, these mechanisms can include,for example, stimulation of angiogenesis, including collateralogenesisand/or increased microvascular density through shear stress andcavitation.

In some embodiments, disclosed herein are methods of treating peripheralvascular disease. The methods can stimulate angiogenesis and/orcollaterogenesis within a patient in some cases. The methods can includeproviding a wearable non-invasive device. The device can include, forexample, a housing material that can be flexible in some cases. Thedevice can also include one transducer, or an array of ultrasoundtransducers operably attached to the housing material. The method canalso include positioning the device and the transducer or array oftransducers proximate a skin surface of a patient above at least onetarget site angiosome below the knee where angiogenesis is desired, andsuch that the flexible housing material and the array of ultrasoundtransducers substantially conforms to the skin surface of one or more ofthe calf, ankle, and foot of the patient, which can eliminate sharpangles present between adjacent panels of a housing, in some cases. Themethod can be utilized over a set period of time and number of treatmentsessions to cause a therapeutically effective amount of ultrasonicenergy to be directed toward the target site angiosome, therebystimulating cavitation and shear stress within tissue at the target siteangiosome, thereby promoting angiogenesis and/or collaterogenesis withinthe patient. In some embodiments, the ultrasonic energy can have asurface intensity:depth ratio of between about 0.10 W/cm³ and about 0.60W/cm³. In some embodiments, the ultrasonic energy has a frequency ofbetween about 0.5 MHz and about 5 MHz, between about 1 MHz and about 3MHz, or other frequencies as disclosed elsewhere herein. The ultrasonicenergy can have, for example, a peak negative pressure of between about1 MPa and about 4 MPa. The method can also include positioning the arrayof transducers above at least two target site angiosomes. The targetsite angiosomes can include, for example, the medial calcaneal arteryangiosome; the medial plantar artery angiosome; the dorsalis pedisartery angiosome; the lateral calcaneal artery angiosome, and theanterior perforating branch artery angiosome. The method can alsoinclude measuring the reflected acoustic power of the ultrasonic energyfrom at least one transducer of the array of transducers. The method caninclude discontinuing directing the ultrasonic energy from the at leastone transducer found to have a reflected acoustic power above apredetermined threshold. In some embodiments, the method can includemeasuring blood flow in real time over the at least one angiosome, andadjusting parameters of the ultrasonic energy based on the measuredblood flow. The surface area of the transducer or array of transducerscan cover, for example, at least about 40%, 60%, 80%, or more of asurface area of the entire wearable device.

The modality could be, for example, therapeutic ultrasound (TUS - andmay incorporate HIFU, LIPUS, and/or other pulsed or continuous waveacoustic energies), and be configured to promote angiogenesis and/orcollaterogenesis within a patient. Methods can include in someembodiments stimulating angiogenesis and/or collaterogenesis within apatient, including providing a wearable non-invasive device that is notcatheter-based or invasive in some cases, and comprising at least oneultrasound transducer or an array of transducers; positioning the atleast one ultrasound transducer proximate a skin surface of a patientabove a target site below the skin surface where angiogenesis isdesired; and causing a therapeutically effective amount of ultrasonicenergy over a set time period to be directed toward the target site,thereby stimulating angiogenesis within the patient. In someembodiments, the energy can be delivered with a device that is notnecessarily wearable or does not have wearable components, e.g.,endovascularly from one, two, or more transducers or a transducer arraycoupled to a catheter, with energy delivery and other parameters asdescribed for example herein. The wearable device can be activatedcontinuously (in pulsed form) for at least 1, 2, 4, or more hours daily,or for overnight use for example. The wearable device can becircumferentially or non-circumferentially wrapped around a portion of abody, such as an extremity of the patient. The extremity could be anupper or lower extremity, unilaterally or bilaterally. In someembodiments, the skin surface is on at least one of a thigh, a calf, anankle, or the foot of a patient. The method can involve moving thedevice in a cranio-caudal direction during use, and/or rotating thedevice around a longitudinal axis of the device during use. Positioningthe at least one ultrasound transducer proximate a skin surface caninclude aligning a positioning guide on a sleeve of the deviceanteriorly or posteriorly with respect to an extremity of the patient.The at least one ultrasound transducer or array of transducers can bepositioned, for example, on the medial surface of the patient’s thigh;on the posterior surface of the patient’s calf; on the anterior surfaceof the patient’s ankle; on the inferior/plantar surface of the patient’sfoot; on the neck proximate the carotid artery; or on the torsoproximate the renal artery. Blood flow at the target site can bemeasured, and the ultrasonic energy increased or decreased based off themeasured blood flow. The method can also include sensing the temperatureat the skin surface, and decreasing or terminating the ultrasonic energydelivery if the temperature is above a pre-determined level.

In some embodiments, in some systems and methods the wearable device canbe applied to the patient for treatment at least 3 days a week, or atleast about 1 month. The ultrasonic energy can be delivered below thesensation threshold of the patient in some cases. The transducer orarray, or the entire device could include, for example, solidpiezoelectric materials and a backing material. The device can include,in some cases, a flexible surface to allow for conformal or flexibleapposition to the skin surface of the patient. The method can alsoinvolve assessing for the presence of bone in a near-field via animaging modality, and adjusting the positioning of the transducer or aparameter of the ultrasonic energy if bone is identified in thenear-field. Ultrasound parameters can be adjusted such that the targetsite is in a near-field, and bony structures of the patient are in afar-field. Data regarding a therapy session can be recorded, andtransmitting the data to a remote device in some cases. A user interfacecan be activated to adjust a parameter regarding the ultrasonic energybased on the comfort level of the patient. In some embodiments, thetherapeutically effective amount of ultrasonic energy also stimulatesvasodilation at the target site within about 24 hours of a therapysession. Systems and methods as disclosed herein can be utilized for awide variety of indications, including the treatment or prevention ofacute limb ischemia, chronic limb ischemia, diabetic foot ulcers, orrestless legs syndrome. A target site can include, or be substantiallylimited to, for example, the gastrocnemius muscle, soleus muscle,posterior tibial artery, plantar arch arteries, or others. In someembodiments, an array of transducers can be provided that can include(or the transducer housing or backing material connecting thetransducers can include), for example, circular, oval, spherical,rectangular, rhomboid, trapezoidal, or other cross-sections. In someembodiments, the method can include sensing reflected power back at thetransducer or transducer array in real time, and discontinuing thetherapy if the reflected power sensed is greater than a predeterminedvalue. In some embodiments, the plurality of target sites can includeone or more of the medial thigh, posterior calf, anterior calf, dorsalmidfoot, and plantar midfoot. The therapeutically effective amount ofultrasonic energy can be directed to the plurality of target sitesconcurrently, or one, two, or more at a time. Some embodiments caninclude measuring perfusion at the target site in real time orsubstantially real time, and outputting a parameter relating toperfusion onto a display. In some aspects, a parameter of the ultrasonicenergy can be adjusted after measuring perfusion at the target site. Theultrasonic energy can include, for example, a surface intensity:depthratio of between about 0.10 W/cm³ and about 0.60 W/cm³.

In some embodiments, disclosed are systems for stimulating angiogenesiswithin a patient. The systems can include a wearable non-invasive deviceincluding an elastic sleeve. The system can also include at least oneTUS transducer or array configured to be positioned proximate a skinsurface of a patient above a target site below the skin surface whereangiogenesis is desired. The ultrasound transducer/array can beconfigured to cause a therapeutically effective amount of ultrasonicenergy over a set time period to be directed toward the target site,thereby stimulating cavitation and shear stress within tissue at thetarget site, thereby promoting angiogenesis within the patient. Aportable power supply can be attached to the sleeve. In someembodiments, an adhesive gel pack can be optionally positionable betweenthe at least one ultrasound transducer and the elastic sleeve.

In some embodiments, the at least one TUS transducer can be configuredto deliver ultrasonic energy at a frequency of between about 500 kHz andabout 5 MHz, or between about 1 MHz and about 3 MHz or other values asdescribed elsewhere herein. The at least one TUS transducer can beconfigured to deliver ultrasonic energy at a PRF of between about 1 Hzand about 3 Hz in some cases, or other values as described elsewhereherein. The at least one TUS transducer can be configured to deliverultrasonic energy at a pulse duration of between about 1 ms and about 10ms, or other values as described elsewhere herein. In some embodiments,the at least one TUS transducer is configured to deliver ultrasonicenergy at a duty factor of between about 0.5% and about 2%, or othervalues as described elsewhere herein. The at least one TUS transducercan be configured to deliver ultrasonic energy at a peak negativepressure of between about 1 MPa and about 4 MPa, or other values asdescribed elsewhere herein. The at least one TUS transducer can beconfigured to deliver ultrasonic energy at a an acoustic dose of betweenabout 250-2000 mW/cm², and a surface intensity and/or derated Isppa ofbetween about 50-1000 W/cm².

In some embodiments, disclosed herein is a wearable system forstimulating angiogenesis within a patient. The system can include awearable non-invasive device that can include an elastic sleeve devicecomprising a proximal end and a distal end. The system can also includean array of TUS transducers configured to be positioned proximate a skinsurface of a patient above at least one below-the-knee target siteangiosome where angiogenesis is desired. The array of ultrasoundtransducers can be configured to substantially conform to a calf, ankle,and/or foot of the patient. The array of ultrasound transducers can befurther configured to cause a therapeutically effective amount ofultrasonic energy over a set time period to be directed toward thetarget site, thereby stimulating cavitation and shear stress withintissue at the target site, thereby promoting angiogenesis within thepatient at the target site. The distal end of the sleeve, sock, or otherwearable housing can have a closed or open distal end. The system can beconfigured in some cases to have any number of the followingnon-limiting parameters: a surface intensity:depth ratio of less thanabout 0.60 W/cm3; a frequency of between about 0.5 MHz and about 5 MHzor between about 1 MHz and about 3 MHz; and/or a peak negative pressureof between about 1 MPa and about 4 MPa. In some embodiments, at leastsome transducers of the array of transducers are directly adjacent eachother, or spaced apart by no more than about 10 cm, 8 cm, 6 cm, 4 cm, 2cm, 1 cm, 0.5 cm, 0.1 cm, or less from each other.

In some embodiments, an ultrasound imaging component may be combinedinto the device using the same transducer(s) that provide therapy, orseparate transducers. This may use A-, M- or B-mode ultrasound imagingto assess for high acoustic reflection in the near-field which wouldsuggest that there is bone or other more echogenic material in thenear-field of the treatment area.

In some embodiments, wearable systems and methods can include any numberof elements or features or combinations thereof as disclosed herein.

BRIEF DESCRIPTION OF THE DRAWINGS

The patent or application file contains at least one drawing executed incolor. Copies of this patent or patent application publication withcolor drawing(s) will be provided by the Office upon request and paymentof the necessary fee.

FIGS. 1 and 2 illustrates potential mechanisms of action of a TUSwearable device.

FIG. 3 illustrates sample waveforms of TUS and SWT, respectively.

FIG. 3A schematically illustrates 3 main arteries and 6 angiosomes ofthe below-the-knee lower extremity.

FIGS. 4A-C schematically illustrate embodiments of a wearableultrasound-based sleeve for treating PAD, according to some embodimentsof the invention. FIG. 4A demonstrates a three-component embodiment withelastic sleeve, battery/interface console, and single elementtransducer. FIG. 4B demonstrates an embodiment with an 8-transducerarray positioned over the posterior calf. FIG. 4C demonstratespositioning of transducer array over the gastrocnemius and soleusmuscles for the calf embodiment. FIG. 4D illustrates a sleeve in theform of a sock that can include a closed distal end as illustrated. FIG.4E illustrates an embodiment similar to FIG. 4D with differentdimensions for the array. FIG. 4F schematically illustrates anembodiment of a wearable stocking with an open-toed distal end (althoughit can be closed-toed in other embodiments as mentioned herein). FIG. 4Gillustrates a cross-section of a wearable device that includes a textileweave that can surround and/or overlap a transducer array and/or gelmedia layer as illustrated.

FIG. 4H illustrates a cross-section through a calf, illustratinganterior and posterior tibial vessels and surrounding structures. FIG.4I illustrates inferior and superior views of the foot and targetlocations for the delivery of therapeutic energy thereto.

FIGS. 5A-5D schematically illustrate embodiments of wearableultrasound-based sleeves for treating PAD, sized and configured forplacement around the thigh, calf, and plantar mid-foot respectively.Also illustrated are various non-limiting arterial vessels that may beinvolved in PAD and treated using systems and methods disclosed herein,also in FIGS. 5E-5F.

FIG. 6A illustrates a schematic cross-sectional view of wearableultrasound-based sleeves, and a transducer positioned between the sleeveand the skin surface. FIG. 6B illustrates an ultrasound gel packpositioned in between the ultrasound transducer and the sleeve,according to some embodiments of the invention. FIG. 6C demonstrates acircumferential water or gel sleeve that couples the transducer(s) tothe skin.

FIGS. 7A-7B schematically illustrates two embodiments of the wearableultrasound sleeve displayed in unwrapped form. FIG. 7A includes anindicia of positioning, positioning guides, a transducer dock, andbattery dock. FIG. 7B demonstrates an embodiment of the sleeve with an8-transducer array, positioning line, and battery/interface.

FIGS. 8A-8D illustrates non-limiting positions of an ultrasoundtransducer adjacent the skin surface of an anatomical target location.In FIG. 8A, the transducer (or array) is illustrated positioned alongthe medial aspect of the thigh, maintaining the femoral artery in theacoustic near-field and femur in far-field so as to maximize vascularexposure and minimize bone exposure of acoustic tissue. In FIG. 8B, thetransducer (or array) is positioned over the posterior aspect of thecalf, maintaining the gastrocnemius, soleus, and posterior tibial arteryin the near-field, and tibia and fibula in far-field. In FIG. 8C, thetransducer (or array) is positioned over the plantar mid-foot,maintaining the plantar arterial arch in the near-field and metatarsalsin the far-field. FIG. 8D schematically illustrate additional vessels onthe dorsal and plantar surfaces of the foot.

FIG. 9 illustrates an embodiment of a single-element transducer having acircular geometry with a spherical curve, as well as a rectangulargeometry with a cylindrical curve. The transducer could in someembodiments include a taper with multiple radii of curvature includingfirst and second radii of curvatures as illustrated.

FIGS. 10A-10F illustrates arrays of transducers in a polygonal shape,connected with a wearable component, such as a sleeve.

In some embodiments, each transducer could have a duty cycle that is upto 1/(total number of transducers), for example in an array of 8transducers, each may have up to a 12.5% duty cycle. FIGS. 10A-Bdemonstrate two shapes of arrays of 16 circular, 4 cm diametertransducers (FIG. 10A being a trapezoidal shape, and 10B being a diamondor truncated diamond shape). FIGS. 10C-D demonstrate two shapes ofarrays of 8 circular, 6 cm diameter transducers (FIG. 10C being atrapezoidal shape, and FIG. 10D being a diamond or truncated diamondshape). FIGS. 10E-F demonstrate two shapes of arrays of 4 circular, 9 cmdiameter transducers (with FIG. 10E being a trapezoidal shape and FIG.10F being a diamond or truncated diamond shape).

FIG. 11 illustrates non-limiting embodiments of a matrix of anatomiclocations of transducer/array placement to optimize macrovascularcollateralogenesis and microvascular angiogenesis.

DETAILED DESCRIPTION

Disclosed herein are systems and methods including wearable,non-invasive ultrasound modalities for treating a variety of medicalconditions, including but not limited to PVD. The devices can beadvantageously configured to achieve a variety of beneficial clinicaleffects, including but not limited to angiogenesis via collateralizationand/or an increase in microvascular density.

SWT and TUS treatments of both CAD and PAD to date have been limited bysmall effect size. Effects of SWT on PAD patients were modest, andanimal studies have shown only a 24% increase in pedal blood flow withTUS and 18% with SWT.

Conventional ultrasound-based treatments for both CAD and PAD have beenlargely limited by the fact that treatment requires a healthcareprovider to be present to position and hold the device. By providing awearable TUS sleeve that positions and fixes the ultrasound transduceror transducer array in place, treatment may be provided for up toseveral hours (e.g., 20 min - 24 hours duration or more, includingovernight therapy) at a time, thereby increasing treatment duration.Providing extended treatment duration using wearable ultrasound-baseddevices at predetermined parameters can in some embodiments can lead toprofound and unexpected improvements in therapeutic results, includingbut not limited to increased blood flow from, for example, angiogenesis(forming new blood vessels). FIGS. 1 and 2 illustrates potentialmechanisms of action of, for example, TUS therapy. Not to be limited bytheory, such a device can be configured to increase vascularpermeability from cavitation microbubbles interacting with theendothelium, and shear stresses from ultrasound waves directly ontoendothelial surfaces, which can stimulate the production and/or releaseof growth factors, angiogenic factors and signaling molecules such asincrease tissue vascular endothelial growth factor (VEGF), endothelialnitric oxide synthase (eNOS), basic fibroblast growth factor (bFGF),adenosine triphosphate (ATP), for example, leading to angiogenesisand/or collateralogenesis. Longer duration treatments can advantageouslyincrease the local and possibly also circulating levels of theseangiogenic factors among others, leading to collateralogenesis andincreased microvascular density in PAD.

In contrast, some conventional systems and methods merely increasenitric oxide within tissue, thus increasing blood flow temporarily viavasodilation. However, these effects and symptomatic relief can betransient in nature and be limited to the duration of the treatmentsession or a short period thereafter. Not to be limited by theory,achievement of vasodilation without long-term angiogenic effects inconventional systems can be due to insufficient peak acoustic pressuresand/or durations of therapy, among other reasons. As illustrated inFIGS. 1 and 2 , additional mechanisms may involve acute vasodilationlasting at least 1 minute and up to 24 hours, to provide acutesymptomatic relief prior to angiogenesis, such as for at least about 1,2, 3, 4, 5, 10, 15, 20, 30, 45, 60 or more minutes, or at least about 2,3, 4, 6, 8, 12, 16, 18, or 24 hours, or ranges incorporating any two ofthe aforementioned values.

Not to be limited by theory, long-term angiogenesis andcollateralogenesis can occur, for example, through two or moreultrasound-mediated mechanisms, as illustrated, for example, in FIGS. 1and 2 . The first mechanism is cavitation: in some embodiments, TUSwaves with sufficient peak negative pressure may cause dissolved gas tocome out of solution in blood and tissue, and to convert intomicrobubbles. In response to TUS, these bubbles then volumetricallyoscillate and/or burst, interacting with vascular endothelial cells,increasing vascular permeability, and triggering angiogenesis andcollateralogenesis. While the process of cavitation is well-described,the inventors are not aware of previous techniques which specificallyharness this process to promote vascular permeability and thusangiogenesis/collateralogenesis. This mechanism may also triggerup-regulation of several molecular mediators ofangiogenesis/collateralogenesis as described further herein. In someembodiments, p- can be selected to promote cavitation, vascularpermeability and angiogenesis/collateralogenesis without leading toharmful or lethal vascular damage.

A second mechanism is shear stress: in some embodiments, TUS waves of adesired frequency and sufficient amplitude can directly interact withendothelial cells, triggering shear stress signaling pathways, which maylead to angiogenesis and collateralogenesis. While the effects ofendothelial shear stress on vasodilation and angiogenesis has beendescribed, the inventors are not aware of previous techniques utilizingTUS to specifically increase endothelial shear stress, leading tovasodilation, collateralogenesis and angiogenesis.

TUS and SWT can in some embodiments lead to tissue-specific increases inangiogenic factors (or upregulation of receptors of growth factors) suchas vascular endothelial growth factor (VEGF), e.g., VEGF-A and itsreceptor, FLT-1; fibroblast growth factor (FGF), e.g., bFGF the nitricoxide pathway; and stem cell differentiation. Systems and methods asdisclosed herein can also potentially modulate (e.g., decrease orincrease depending on the factor) levels of other factors including butnot limited to VEGFR, bFGF, HIF-1-alpha, Egln1, NRP-1, Ang1, Ang2, PDGF,PDGFR, TGF-beta, endoglin, CCL2, ephrin, histamine, integrins,plasminogen activators, plasminogen activator inhibitor-1, eNOS, iNOS,COX-2, AC133, ID1/ID3, or class 3 semaphorins, among others. In someembodiments, the ultrasound-based therapy can change, such as increaseor decrease circulating levels, mRNA, or other proxies of the foregoingmarkers by about or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%,40%, 45%, 50%, 75%, 100%, or more after therapy compared to pre-therapyvalues. In some embodiments, blood flow at a desired target location canincrease by about or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%,40%, 45%, 50%, 75%, 100%, or more after therapy compared to pre-therapyvalues, and remain increased for about or at least about 6 hours, 12hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 1month, 3 months, 6 months, 1 year, or even more. In some embodiments,the ultrasonic energy can be therapeutically effective to provideanti-inflammatory effects, stem cell differentiation, satellite celldifferentiation, and/or modulation of prostacyclin pathways.

Endothelial cells line mature blood vessels and typically do notproliferate. However, if endothelial cells are activated by anangiogenic growth factor, they can proliferate and migrate intoun-vascularized tissue to form new blood vessels. Blood vessels aresurrounded by biological tissue in an extracellular matrix. Theformation of new blood vessels is a function of the interactions betweenendothelial cells and the interaction of the endothelial cells with theextracellular matrix. These interactions are regulated by receptors onthe surface of endothelial cells, which are sensitive to particularmolecules such as angiogenic growth factors. Shear stress induced onendothelial cells by pressure waves can potentially reduce endothelialdysfunction and promotes angiogenesis. This effect can correlate in somecases with both with TUS amplitude (p⁻), as well as frequency (withgreater shear stress at lower frequencies). Sub-lethal microvascularpermeability can result from the process of “cavitation”: the formationand subsequent violent vibration/collapse of gas bubbles coming out ofsolution in vessels and interacting with the vessel wall via multiplemechanisms (e.g., FIGS. 1 and 2 ). This can be in some cases athreshold-based phenomenon, which occurs at a given p⁻ and increaseswith greater intensity. In other words, angiogenesis can be caused bystress/cavitation leading to endothelial signaling, growth factorincrease, and new capillary and large vessel growth.

In some embodiments, a wearable ultrasound-based device can be worn andoperated for about or at least about 5, 10, 15, 20, 30, 40, 50, or 60minutes daily, or about or at least about 2, 3, 4, 5, 6, 7, 8, 9, 10,11, 12, 15, 18, 24, or more hours at a time (or ranges including any twoof the aforementioned values), either cumulatively in multiple treatmentsessions, or continuously in some cases. In some embodiments, the devicecan be worn and operated for between about 10 minutes and about 20minutes; between about 20 minutes and about 40 minutes; between about 30minutes and about 60 minutes; between about 1 hour and about 2 hours;between about 2 hours and about 4 hours; or between about 4 hours andabout 8 hours per treatment session. However, in some embodiments thedevice is worn and operated for about, or no more than about 24, 18, 15,12, 11, 10, 9, 8, 7, 6, 5, 4, 3, or 2 hours at a time. In someembodiments, the device can be worn and operated about or at least aboutonce, twice, three times, or more daily; or once, twice, or three timesweekly. In some embodiments, the device can be worn and operatedovernight and/or while a patient is sleeping, such as between about 4hours and about 10 hours, or between about 5 hours and about 9 hoursdaily or nightly, 5-7 times a week, or during the day while notsleeping.

In some embodiments, the wearable devices allow for convenientdose-response titrations to readily be performed without requiring longtreatments to be performed by a medical provider using timeframes suchas disclosed above.

In some embodiments, the ultrasound modality could be TUS, SWT, or adual-mode combination thereof using one or a plurality of ultrasoundtransducers. In some embodiments, use of TUS (which may include HIFU,LIPUS, or other pulsed or continuous wave acoustic energies) instead ofSWT can advantageously allow for titration of one, two, or more acousticparameters to achieve a desired angiogenic effect as discussed herein.The parameters can include, for example, frequency, pulse repetitionfrequency (PRF), pulse duration, duty factor, and pressure amplitudes(peak positive and negative pressures; p⁺, p⁻). Additionally, in somecases TUS can be advantageous as it allows application of multiplesound/pressure waves in each pulse; SWT provides a single pressure wave.

Due to differences in the SWT and TUS waveforms, SWT parameters can onlybe adjusted to modulate pulse repetition frequency and acousticamplitudes. FIG. 3 illustrates sample waveforms of TUS and SWT,respectively. In contrast, TUS additionally allows modulation ofultrasound frequency, pulse duration, duty factor), parameters may betitrated to improve these angiogenic effects (low frequency, high p⁻),while avoiding acoustic intensities that may lead to thermal orcavitation-based damage. However, embodiments can also include SWT,including parameters for pulse repetition frequency and amplitudes asdescribed herein. Furthermore, if regulatory requirements specify amaximal acoustic intensity (p⁻, W or W/cm²) to avoid cavitation-baseddamage, this parameter can be fixed while others can be adjusted tomaximize effect. Finally, adverse effects of ultrasound are mostprominent in gas-filled organs such as the lung and gastrointestinaltract in which gas unpredictably reflects and may intensify sound waves.Targeting lower extremity muscle and vasculature, which are generallyfree of air, can advantageously avoid these effects in some cases.

The above-described potential mechanisms of TUS-induced cavitation andshear stress can be dependent upon p- and frequency, respectively,although total dose of TUS is also determined by pulse repetitionfrequency (PRF), duty factor (% of time that TUS is active), andduration of therapy (time that patient wears the sleeve). Each of theseTUS parameters has a toxic-therapeutic window, which can advantageouslybe adjusted for a desired clinical result given its wearable design andtitratability of TUS parameters.

Many of the TUS mechanisms promoting angiogenesis and collateralogenesiswith long-term use are also associated with acute, short-termvasodilation. Thus, certain embodiments of the device and method may beused to immediately or quickly increase perfusion for the treatment ofacute limb ischemia, such as about or within about 1 minute, 5 minutes,10 minutes, 15 minutes, 30 minutes, 60 minutes, 2 hours, 4 hours, 6hours, 12 hours, 18 hours, or 24 hours after the onset of therapy, aswell as have longer-lasting effects as disclosed herein. In someembodiments, systems and methods as disclosed herein can include onlyTUS and not SWT, only SWT but not TUS, or a combination of both SWT andTUS.

Frequency

In some embodiments, the frequency of ultrasound provided could bebetween about 250 kHz and about 3 MHz, between about 250 kHz and about 1MHz, between about 250 kHz and about 500 kHz, between about 1 MHz andabout 3 MHz, between about 750 kHz and about 1.25 MHz, between about 500KHz and about 1 MHz, between about 2 MHz and about 3 MHz, or overlappingranges thereof. Not to be limited by theory, lower frequencies canadvantageously increase the shear stress mechanism of action. In someembodiments, lower frequencies could also penetrate more deeply intoissue, although frequencies that are too low may penetrate too deeplyand reach bone on the opposite end of the desired PAD field. In someembodiments, the treatment frequency could be between about 250 kHz andabout 1 MHz on the thigh (deeper field from the skin of the medial thighto the femur); between about 500 kHz and about 1.25 MHz on the calf(deep field from the skin of the posterior calf to the tibia); orbetween about 750 kHz and about 1.5 MHz on the ankle (shallow field fromthe skin of the anterior ankle to the bones), and between about 1 MHzand about 3 MHz on the plantar surface of the foot (even shallower fieldfrom skin to the tarsal and metatarsal bones), or between about 500 kHzand about 3 MHz, between about 1 MHz and about 3 MHz, and/or at leastabout 500 kHz or 1 MHz in any of the aforementioned locations. In someembodiments, the frequency provided can be about, more than about, or nomore than about 200 KHz, 250 kHz, 300 kHz, 350 kHz, 400 kHz, 450 kHz,500 kHz, 550 kHz, 600 kHz, 650 kHz, 700 kHz, 750 kHz, 800 kHz, 850 kHz,900 kHz, 950 kHz, 1 MHz, 1.1 MHz, 1.2 MHz, 1.3 MHz, 1.4 MHz, 1.5 MHz,1.6 MHz, 1.7 MHz, 1.8 MHz, 1.9 MHz, 2 MHz, 2.1 MHz, 2.2 MHz, 2.3 MHz,2.4 MHz, 2.5 MHz, 2.6 MHz, 2.7 MHz, 2.8 MHz, 2.9 MHz, 3 MHz, 3.1 MHz,3.2 MHz, 3.3 MHz, 3.4 MHz, 3.5 MHz, 4 MHz, 5 MHz, 10 MHz, 15 MHz, 20MHz, 25 MHz, 30 MHz, 35 MHz, 40 MHz, 45 MHz, 50 MHz, 60 MHz, 70 MHz, 80MHz, 90 MHz, 100 MHz, or ranges incorporating any of the foregoingvalues. In some embodiments, systems and methods can provide a pluralityof different alternating frequencies during treatment, such as 2, 3, 4,or more different frequencies.

Pulse Repetition Frequency

In some embodiments, the pulse repetition frequency can be between about0.1 Hz and about 100 Hz, between about 1 Hz and about 3 Hz, betweenabout 0.1 Hz and about 1 Hz, between about 0.5 Hz and about 2 Hz,between about 1 Hz and about 5 Hz, between about 5 Hz and about 10 Hz,between about 10 Hz and about 20 Hz, between about 20 Hz and about 100Hz, or overlapping ranges thereof. Not to be limited by theory, higherPRF can increase total delivered ultrasound energy and angiogeniceffect, but may also increase transducer heating. In some cases, a verylow PRF may lead to insufficient cavitation and shear stress (and only ashort-term vasodilation effect), while very high PRF may lead in somecases to transducer warming, lethal vascular damage (including possibledissection, stenosis, or thromboembolism), microhemorrhage, possiblenerve damage, pain, fat or other tissue necrosis, apoptosis, and/or scarformation. In some embodiments, the PRF provided can be about, more thanabout, or no more than about 0.1 Hz, 0.5 Hz, 1 Hz, 1.5 Hz, 2 Hz, 2.5 Hz,3 Hz, 3.5 Hz, 4 Hz, 4.5 Hz, 5 Hz, 6 Hz, 7 Hz, 8 Hz, 9 Hz, 10 Hz 12 Hz,14 Hz, 16 Hz, 18 Hz, 20 Hz, 25 Hz, 30 Hz, 35 Hz, 40 Hz, 45 Hz, 50 Hz, 60Hz, 70 Hz, 80 Hz, 90 Hz, 100 Hz, 110 Hz, 120 Hz, or ranges incorporatingany of the foregoing values. In some embodiments, systems and methodscan provide a constant or variable PRF.

Pulse Duration

In some embodiments, the pulse duration can be between about 1 µs (3oscillations of 3 MHz) and about 100 ms, between about 1 ms and about 10ms, between about 1 µs and about 100 µs, between about 100 µs and about500 µs, between about 500 µs and about 1 ms, between about 1 ms andabout 5 ms, between about 5 ms and about 20 ms, between about 10 ms andabout 50 ms, between about 25 ms and about 100 ms in some embodiments,or overlapping ranges thereof. Not to be limited by theory, longerpulses can increase total delivered ultrasonic energy and likelyangiogenic effect, but may also increase transducer heating. In somecases, a very low pulse duration may lead to insufficient cavitation andshear stress (and only a short-term vasodilation effect), while veryhigh pulse durations may lead in some cases to transducer warming,lethal vascular damage (including possible dissection, stenosis, orthromboembolism), microhemorrhage, possible nerve damage, pain, fat orother tissue necrosis, apoptosis, and/or scar formation. In someembodiments, the pulse duration provided can be about, more than about,or no more than about 1 µs, 5 µs, 10 µs, 25 µs, 50 µs, 100 µs, 250 µs,500 µs, 750 µs, 1 ms, 2 ms, 3 ms, 4 ms, 5 ms, 6 ms, 7 ms, 8 ms, 9 ms, 10ms, 15 ms, 20 ms, 25 ms, 30 ms, 35 ms, 40 ms, 45 ms, 50 ms, 60 ms, 70ms, 80 ms, 90 ms, 100 ms, 110 ms, 120 ms, or ranges incorporating any ofthe foregoing values. In some embodiments, systems and methods canprovide a constant or variable pulse duration.

Duty Factor

In some embodiments, the duty factor can be between about 0.1% and about50%, such as between about 0.5% and about 2%, between about 0.1% andabout 0.5%, between about 1% and about 5%, between about 2% and about10%, between about 5% and about 20%, between about 20% and about 50%, orabout 1% in some embodiments, or overlapping ranges thereof. Higher dutyfactor can increase total delivered ultrasonic energy and likelyangiogenic effect, but may also increase transducer heating. In somecases, a very low duty factor may lead to insufficient cavitation andshear stress (and only a short-term vasodilation effect), while veryhigh duty factors may lead in some cases to transducer warming, lethalvascular damage (including possible dissection, stenosis, orthromboembolism), microhemorrhage, possible nerve damage, pain, fat orother tissue necrosis, apoptosis, and/or scar formation. In someembodiments, the duty factor provided can be about, more than about, orno more than about 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%,0.8%, 0.9%, 1%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%,2%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%,12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 25%, 30%, 35%, 40%, 45%,50%, or ranges incorporating any of the foregoing values.

For embodiments incorporating a phased array of transducers, asdemonstrated in FIG. 10 , each transducer could have a duty cycle thatis up to about 1/(total number of transducers), for example in an arrayof 8 transducers, each may have up to about a 12.5% duty cycle. Eachtransducer could have equal duty cycles, or unequal duty cycles in someembodiments.

Peak Negative Pressure

In some embodiments, the peak negative pressure (p⁻; greater p- can beassociated with more shear stress and cavitation, and angiogenic effect,although high p- can theoretically lead to vascular damage) can bebetween about 2 MPa and about 20 MPa, between about 6 MPa and about 10MPa, between about 2 MPa and about 4 MPa, between about 1.5 MPa andabout 4 MPa, between about 1 MPa and about 4 MPa, between about 2.5 MPaand about 3.5 MPa, between about 3 MPa and about 5 MPa, between about 4MPa and about 6 MPa, between about 5 MPa and about 7 MPa, between about7 MPa and about 10 MPa or less than about 4 MPa in some embodiments. Forclarity, the minus signs preceding the peak negative pressure disclosedherein are omitted - for example, a peak negative pressure of 4 MPa (canbe denoted elsewhere as -4 MPa) as described herein is more negativethan a peak negative pressure of 1 MPa (can be denoted elsewhere as -1MPa). In some embodiments, the p⁻ may be selected to maximize sub-lethalcavitation. In some cases, a very low p⁻ may lead to insufficientcavitation and shear stress, while very high p⁻ may lead in some casesto transducer warming, lethal vascular damage (including possibledissection, stenosis, or thromboembolism), microhemorrhage, possiblenerve damage, pain, fat or other tissue necrosis, apoptosis, and/or scarformation. In some embodiments, the p⁻ provided can be about, more thanabout, or no more than about 0.5 MPa, 1 MPa, 1.5 MPa, 2 MPa, 2.5 MPa, 3MPa, 3.5 MPa, 4 MPa, 4.5 MPa, 5 MPa, 5.5 MPa, 6 MPa, 6.5 MPa, 7 MPa, 7.5MPa, 8 MPa, 8.5 MPa, 9 MPa, 9.5 MPa, 10 MPa, 10.5 MPa, 11 MPa, 12 MPa,13 MPa, 14 MPa, 15 MPa, 16 MPa, 17 MPa, 18 MPa, 19 MPa, 20 MPa, 21 MPa,22 MPa, 25 MPa, or ranges incorporating any of the foregoing values.

Acoustic Intensity

In some embodiments, the ultrasound parameters may be configured toprovide an acoustic dose as calculated at the surface, or the targettissue as described herein to specifically promote angiogenesis. In someembodiments, the acoustic dose as calculated at either the surface, orby derated I_(spta) of between about 250 mW/cm² and about 5,000 mW/cm²,between about 250 mW/cm² and about 720 mW/cm², between about 720 mW/cm²and about 5000 mW/cm², between about 500 mW/cm² and about 1,000 mW/cm²,between about 750 mW/cm² and about 1,500 mW/cm², between about 1 W/cm²and about 2 W/cm², between about 2 W/cm² and about 4 W/cm², betweenabout 3 W/cm² and about 5 W/cm², or overlapping ranges thereof. Deratingis a method of making acoustic measurements to account for attenuationin tissue.

In some embodiments, the ultrasound parameters can be configured toprovide intensity at the surface, or a derated Isppa of between about 50W/cm² and about 1000 W/cm², such as between about 50 W/cm² and about 190W/cm², between about 190 W/cm² and about 1000 W/cm², between about 150W/cm² and about 300 W/cm², between about 200 W/cm² and about 500 W/cm²,or between about 500 W/cm² and about 1000 W/cm², or overlapping rangesthereof. In some embodiments, the intensity at the surface, or a deratedI_(spta) provided can be about, more than about, or no more than about150 mW/cm², 200 mW/cm², 250 mW/cm², 300 mW/cm², 350 mW/cm², 400 mW/cm²,450 mW/cm², 500 mW/cm², 550 mW/cm², 600 mW/cm², 650 mW/cm², 700 mW/cm²,750 mW/cm², 800 mW/cm², 850 mW/cm², 900 mW/cm², 950 mW/cm², 1,000mW/cm², 1,250 mW/cm², 1,500 mW/cm², 1,750 mW/cm², 2,000 mW/cm², 2,250mW/cm², 2,500 mW/cm², 2,750 mW/cm², 3,000 mW/cm², 3,250 mW/cm², 3,500mW/cm², 3,750 mW/cm², 4,000 mW/cm², 4,250 mW/cm², 4,500 mW/cm², 4,750mW/cm², 5,000 mW/cm², or ranges incorporating any of the foregoingvalues. In some embodiments, the intensity can be, for example, betweenabout 500 mW/cm² and about 5,000 mW/cm² or between about 1,000 mW/cm²and about 4,000 mW/cm².

In some embodiments, the ultrasound parameters can be configured toprovide a mechanical index (MI, defined as MI = p⁻ _(d)/√f, where p⁻_(d) is derated peak negative pressure and f is frequency) of betweenabout 1 and about 10, such as no more than about 1.9, between about 2and about 10, between about 1 and about 4, between about 4 and about 10,between about 1 and about 2,, between about 2 and about 4, between about3 and about 5, between about 4 and about 8, or between about 5 and about10 in some embodiments, or overlapping ranges thereof. In someembodiments, the mechanical index provided can be about, at least about,or no more than about 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, orranges incorporating any of the foregoing values.

In some embodiments, the system could be configured to deliverultrasound energy in continuous wave (CW) mode, pulse wave (PW) mode, orboth modes.

In some embodiments, the system can be configured to deliver energy witha surface intensity:vessel depth ratio to preferentially treat thetarget tissue (e.g., angiosome(s) in some embodiments). The surfaceintensity:vessel depth ratio can be, for example, about or less thanabout 0.75, 0.70, 0.65, 0.60, 0.55, 0.50, 0.45, 0.40, 0.35, 0.30, 0.25,0.20, 0.15, or 0.10 W/cm³ in some embodiments, or ranges incorporatingany two of the foregoing values, but in some cases at least about 0.05,0.075, 0.10, 0.125, 0.15, 0.175, or 0.20 W/cm³.

In some embodiments, the surface intensity:vessel depth ratio is betweenabout 0.10 W/cm³ and about 0.60 W/cm³, between about 0.10 W/cm³ andabout 0.55 W/cm³, between about 0.125 W/cm³ and about 0.50 W/cm³, orbetween about 0.20 W/cm³ and about 0.50 W/cm³. Not to be limited bytheory, such ratios among others have unexpectedly been found toadvantageously treat PAD and other indications as described herein insome cases by focused ultrasound delivery to the target tissue whileminimizing off-target effects..

In some embodiments, the intensity to surface area of the skin overlyingthe target tissue (e.g., angiosome(s)) can be about, less than about, orat least about 5:1, 4.5:1, 4:1, 3.5:1, 3:1, 2.5:1, 2:1, 1.5:1, 1:1 orless or ranges incorporating any two of the aforementioned values. Suchratios have unexpectedly been found to advantageously treat PAD andother indications as described herein in some cases.

In some embodiments, the maximum power delivered can be, in some cases,between about 30 Amps and about 70 Amps, between about 40 Amps and about60 Amps to foot angiosomes, or about or no more than about 75, 70, 65,60, 55, 50, 45, 40, 35, 30, 25 Amps, or ranges incorporating any two ofthe aforementioned values. In some embodiments, for calf angiosomes, themaximum power delivered can be, for example, between about 100 Amps andabout 250 Amps, between about 125 Amps and about 225 Amps, or about orless than about 250, 245, 240, 235, 230, 225, 220, 215, 210, 205, 200,195, 190, 185, 180, 175, 170, 165, 160, 155, 150, 145, 140, 135, 130,125, 120, 115, 110, 105, 100 Amps, or less, or ranges incorporating anytwo of the aforementioned values.

In some embodiments, the surface power/intensity ratio of the ultrasonicenergy delivered can be about, at least about, or no more than about 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21,22, 23, 24, or 25 cm², or ranges incorporating any two of theaforementioned values and selected to better focus ultrasound to thetarget tissue. In some embodiments, the surface power/intensity ratiocan be, for example, between about 3 cm² and about 25 cm², between about3 cm² and about 5 cm², between about 15 cm² and about 25 cm², or lessthan about 25, 20, 15, 10, 5 cm², or less.

In some embodiments, the therapeutic energy can be focused to aparticular depth depending on the desired target tissue, e.g.,angiosome(s). An angiosome is a 3-dimensional anatomic unit of tissue(including skin, subcutaneous tissue, fascia, muscle, and bone) fed by asource artery and drained by specific veins. The entire body can bedivided into 40 angiosomes. The lower leg, below the knee and includingthe foot includes six angiosomes. The posterior tibial artery feedsthree angiosomes (the medial calcaneal artery angiosome; the medialplantar artery angiosome; and the lateral plantar artery angiosome), theanterior tibial feeds one (the dorsalis pedis artery angiosome), and theperoneal artery feeds two (the lateral calcaneal artery angiosome andthe anterior perforating branch artery angiosome). Any number of theaforementioned angiosomes can be treated to create a therapeutic effect(e.g., increased blood flow, such as via angiogenesis) using systems andmethods as disclosed herein. The posterior tibial artery gives rise to acalcaneal branch, which supplies the medial ankle and lateral plantarheel, a medial branch that feeds the medial plantar instep/arch, and alateral branch that supplies the lateral forefoot, plantar midfoot, andentire plantar forefoot. The anterior tibial artery continues on to thedorsum of the foot as the dorsalis pedis artery. The peroneal arterysupplies the lateral ankle and plantar heel via the calcaneal branch andthe anterior upper ankle via an anterior branch. As such, directingtherapeutic energy to 1, 2, 3, 4, 5, 6, or more angiosomes, such as inthe lower extremity below the knee and/or foot for example canadvantageously promote angiogenesis and other benefits as described forexample herein. Non-limiting examples of angiosomes to be targeted canbe found in the Figures, for example, FIG. 3A, which schematicallyillustrates six angiosomes.

For calf angiosomes, for example, in some embodiments the energy can befocused to a vessel depth of, for example, between about 3 cm and about9 cm, such as between about 4 cm and about 8 cm, or between about 4.5 cmand about 7 cm. In some embodiments, dorsal or plantar foot angiosomes,for example, the energy can be focused to a vessel depth of, forexample, between about 1 cm and about 4 cm, such as between about 1.5 cmand about 3.5 cm, or between about 2 cm and about 3 cm. In someembodiments, the energy can be focused to a vessel depth of about, atleast about, or no more than about 1 cm, 1.5 cm, 2 cm, 2.5 cm, 3 cm, 3.5cm, 4 cm, 4.5 cm, 5 cm, 5.5 cm, 6 cm, 6.5 cm, 7 cm, 7.5 cm, 8 cm, 8.5cm, 9 cm, 9.5 cm, 10 cm, 11 cm, 12 cm, 15 cm, or ranges incorporatingany two of the aforementioned values.

As some non-limiting examples, in some embodiments delivering TUSultrasonic energy to a calf or foot angiosome(s) at a frequency ofbetween about 1 MHz and about 3 MHz, a peak negative pressure of betweenabout 2 MPa and about 4 MPa, energy delivery of between about 1W/cm² andabout 4W/cm² at the target tissue level, and a surface intensity:vesseldepth ratio between about 0.10 W/cm³ and about 0.60 W/cm³, for acumulative total of about or at least about 10, 20, 30, 40, 50, 60, ormore cumulative minutes per week for at least about 1, 2, 3, 4, 5, 6, 7,8, 9, 10, or more weeks can surprisingly and unexpectedly promoteangiogenesis and collaterogenesis in some cases.

Device Design

Conventional SWT and TUS devices have been used for CAD and arepositioned in inter-costal spaces and oriented toward the area ofischemic myocardium by a trained healthcare provider. This can requireat least three times a week clinical visits, which may be an undueburden on patients and the healthcare system. Similarly, SWT devices forPAD are typically too bulky to be affixed to the lower extremity with asleeve, and also require direct positioning.

As such, wearable ultrasound devices, such as TUS devices canadvantageously allow for home-based treatment. FIG. 4A schematicallyillustrates an embodiment of a wearable ultrasound-based device 100 fortreating PAD or another indication, according to some embodiments of theinvention. The device 100 can include a wearable housing or componentsuch as a sleeve 102 as shown, and/or a sock or other form factor. Thewearable housing 102 can include a proximal end 103, distal end 107, andsidewall 105. In some embodiments, the wearable housing such as a sleeve102 can be configured to extend completely circumferentially around abody structure as shown, or only partially circumferentially orpartially around a body structure in other embodiments. The sleeve 102could optionally include a detachable section, such as a zipper,hook-and-loop fastener material, or the like, such as axially along alength of the sleeve in some embodiments for ease in installation orremoval of the device on the patient. The sleeve 102 can be elastic (orinelastic in other embodiments), and include a display and/or control104, and a single element transducer or transducer array 106 operablyattached to an inner and/or outer surface of the sleeve, and connectedto a power source such as a battery, and an ultrasound generator (notshown), which can be integrated or otherwise attached to the wearabledevice in some embodiments. In some embodiments, the transducer ortransducer array 106 can include flexible materials and generallyconform to the shape of the sleeve.

In some embodiments, the device 100 can take the form of a sleeve,stocking, boot, shoe, or other form factor. After diagnosis of anatomicPAD distribution, and selection of desired treatment area in the upperor lower extremity (e.g., the thigh, calf, ankle, or foot), an initialfitting of the device 100 can be performed by the healthcare provider.Thereafter, ultrasonic treatments may take place in the patient’s homewithout requiring the presence of a healthcare provider. In someembodiments, the transducer/array 106 can be reversibly fixed to thelower extremity treatment area with an adhesive coupling gel packapplied between the TUS transducer/array and the patient’s skin. Anadjustable cloth or elastic sleeve around the extremity can be designedto hold the TUS transducer and power source in place along the thigh,calf, ankle, or foot. Within a single anatomic segment (e.g., the thigh,calf, ankle), the TUS transducer and/or sleeve may be moved in anappropriate direction cranio-caudally from treatment-to-treatment totarget the extent of the segment requiring treatment, e.g., one, two ormore specific vascular/tissue compartments (angiosomes) in deep tissue.In one embodiment, this movement could occur in an automated manner withan algorithm and motorized translation of the transducer in the sleeve,thus requiring no repositioning by the provider or patient. Movementcould occur daily or weekly as desired for maximal effect. Within asingle anatomic segment (e.g., thigh, calf, ankle), the TUS transducerand/or sleeve can also be rotated to target the anterior, posterior,medial, or lateral side of the extremity based on desired target.Rotation could also occur in an automated manner as described above.

FIG. 4B demonstrates an embodiment of a device 150 with amulti-transducer array 116 including a plurality of transducers 106(e.g., 8 transducers, or other number as indicated elsewhere herein)positioned over the posterior calf 90. FIG. 4C demonstratesschematically positioning of the transducer array 116 (some componentsof the device not shown for clarity) over the gastrocnemius and soleusmuscles for an embodiment configured to fit around a calf 90. In someembodiments, the array 116 can have a length L of about 30 cm and awidth W of about 20 cm, or other dimensions as described elsewhereherein.

FIG. 4D illustrates schematically anterior and posterior views of awearable device 200 in the form of a sock that can include an openproximal end 205 and a closed (e.g. “closed toe”) distal end 201 asillustrated, and be configured to curve or bend around the ankle area209. The device 200 could have an open distal end 201 in otherembodiments. The wearable device 200 can include a plurality ofultrasound transducers/arrays configured to treat the anterior tibial202, dorsalis pedis 208, posterior tibial 204, and plantar (medial andlateral) 206 angiosomes as schematically illustrated. FIG. 4Eillustrates an embodiment of a wearable device 250 similar to FIG. 4D,except that the array can be an array of transducers 252 measuring, forexample, at least about 1 µm and up to about 1 cm in a dimension, suchas a lateral dimension, resulting in a density of from about 1transducer/cm² up to 1 million transducers/mm² as illustrated. In someembodiments, an array of transducers can cover about or at least about40%, 50%, 60%, 70%, 80%, 90%, 95%, or substantially all of theouter-facing and/or inner-facing surface area of the wearable device. Insome embodiments, the transducer array can circumferentially extendacross about or at least about 40%, 50%, 60%, 70%, 80%, 90%, orsubstantially all of a transverse level of a wearable device.

FIG. 4F schematically illustrates an embodiment of a wearable stockingconfigured to conform to the lower calf and ankles with an open-toeddistal end (although it can be closed-toed in other embodiments asmentioned herein). Also shown schematically is an axially-orientedzipper or similar mechanism for ease in placing or removing the device.The transducer arrays are not shown for clarity.

FIG. 4G illustrates schematically a cross-section of a wearable devicethat includes a textile weave 300 that can surround and/or overlap atransducer array 304 and/or gel media layer 302 as illustrated, suchthat the transducer(s) 304 can be entirely inside or circumscribed bythe textile layer 300. In other embodiments, the gel 302 and transducers304 can be sewn and adhered or otherwise attached instead of interwovenwithin the weave 300 as shown in FIG. 4G.

FIG. 4H illustrates a cross-section through a calf, illustratinganterior and posterior tibial vessels and surrounding structures,including the anterior tibial vessels, fibula, peroneal vessels,interosseous membrane, tibia, posterior tibial vessels, and the soleusmuscle as shown. Schematic representations of a first transducer 202placed over an anterior artery angiosome 2020 to be treated by firsttransducer 202 and a second transducer 204 placed over a posteriorartery angiosome 2040 to be treated by second transducer 204 areillustrated (e.g., such as by embodiments described in connection withFIGS. 4D and 4E above, for example.

FIG. 4I illustrates inferior and superior views of the foot and targetlocations for the delivery of therapeutic energy thereto. The inferiorview of the foot in the lefthand side of FIG. 4I illustrates theposterior tibial artery dividing into medial plantar artery and lateralplantar artery branches, the deep plantar branch of the dorsalis pedisartery, the plantar metatarsal artery, the plantar digital arteries, theplantar arch, and the digital, superficial, and deep branches of themedial plantar artery. The superior view of the foot in the right-handside of FIG. 4I illustrates the anterior tibial artery, medial anteriormalleolar artery, dorsalis pedis artery, medial tarsal arteries,perforating branch of the peroneal artery, the lateral anteriormalleolar artery, the lateral tarsal artery, the arcuate artery, thedorsal metatarsal artery, and the dorsal digital arteries. The shadedareas schematically show parts of angiosomes 2080 (dorsalis pedis) and2060 (medial and lateral plantar) that can be treated via energy fromtransducers such as 208 and 206 respectively in FIGS. 4D and 4E.

Transducers may include solid piezoelectric materials (PZT) with variousbacking materials (air, epoxy, and/or glass microbeads). Otherembodiments may use thick or thin piezoelectric ceramic or polymer filmsthat may be integrated using flexible transducer surfaces to allow forconformal or flexible apposition to the body. Lead zirconate titanate(PZT), lead-free piezoelectric thin films, piezopolymer films,cellulose-based electroactive paper, and other materials may be used.Films may be deposited before device fabrication, and potentialadvantages for application in PAD treatment include lower weight andcost, lower power requirements, wide frequency range of operation, andlarge amplitudes with lower driving voltages and hysteresis. In someembodiments, the device could include a piezo composite material thatincludes piezo ceramic materials together with passive polymers such asepoxies, or active polymers. In some embodiments, the wearable deviceincluding the transducers/transducer arrays can specifically conformand/or circumscribe the calf, ankle, and/or foot or other anatomicallocation of the patient.

In various embodiments, the device may contain a single-elementtransducer or an array of transducers. The single element transducer canbe any desired shape, and in some embodiments have a focusedcylindrical, focused spherical (FIG. 9 ), flat circular, oval, square,or rectangular shape. The transducers can in some cases have a gentlecurvature (to conform to the thigh, calf or ankle). For example, atransducer configured to be placed on a thigh of a patient can have aradius of between about 10 cm and about 30 cm, and have a radius ofcurvature of between about 50 cm and about 300 cm. A transducerconfigured to be placed on a calf of a patient can be configured to havea radius of between about 5 cm and about 15 cm, and a radius ofcurvature of between about 25 cm and about 150 cm. A transducerconfigured to be placed on an ankle or plantar midfoot of a patient canhave a radius of between about 2.5 cm and about 10 cm, and a radius ofcurvature of between about 10 cm and about 100 cm.

In some embodiments, the transducer size can be targeted to a specifictarget, e.g., muscle area for greater tissue coverage. The transducer orarray can be conformable to the anatomical target region for moreefficient and complete energy delivery. In some embodiments, a systemcan include a sleeve holding device to allow for longer treatment withpatient motion. A power supply, such as a battery can allow forportability and enhanced patient comfort, and device placement at thebedside to allow for longer treatment.

In some embodiments, a wearable device configured to conform to thecalf, e.g., a sleeve or sock can have a maximum expanded circumference(or circumference when not in use, or around a calf when in use) ofbetween about 20 cm and about 80 cm, between about 25 cm and about 65cm, or between about 28 cm and about 61 cm in some cases. In someembodiments, an ankle sleeve or sock (or an integrated calf-ankle sleeveor sock) can have a maximum expanded circumference (or circumferencewhen not in use, or around an ankle when in use) of between about 10 cmand about 50 cm, between about 15 cm and about 40 cm, or between about18 cm and about 36 cm in some cases.

The systems can include a portable, removable and/or rechargeableintegrated power source and controller that can connect directly to theultrasound transducer and also fits into the sleeve. The integratedpower source and controller can allow the user and healthcare providerto specify several treatment parameters including one or more of:frequency, treatment time, duty cycle, and/or acoustic intensity. Incertain embodiments, the controller can also allow the user to enterfeedback regarding comfort. The controller can also record and storetime and duration of treatments to allow the healthcare provider tomonitor compliance. This may be done through direct connection to thecontroller for download of usage data, or through wirelesssynchronization to handheld devices or clinical remote monitoringdevices. Similarly, wireless synchronization with a handheld devicecould allow the user to enter acoustic parameters on the handheld deviceto be transmitted to the battery/controller that is incorporated intothe device.

The sleeve or sock could be elastic and one continuous piece, or includehook-and-loop fastener material or other reversible attachmentmechanisms on one or both free ends of the sleeve, akin to a bloodpressure cuff. In some embodiments, the ultrasound-based wearable deviceneed not necessarily take the form of a circumferential sleeve;ultrasound transducers could be placed on the skin surfaces on aC-shaped sleeve that does not completely circumscribe an extremity orother body region, or discrete bandages (self-adhesive stickers,patches, or decals for example) incorporating an ultrasound transducer,for example. In some embodiments, an ankle or midfoot transducer/arraymay be incorporated as part of a “boot” that fits around only part of,or the entire foot, maintaining the transducer in desired anteriorposition and also containing the battery/generator pack with no exposedwiring in some cases. In some embodiments, transducers or an array oftransducers can deliver energy across the targeted angiosomes asdescribed herein.

Atherosclerotic burden in PAD can be localized to larger vessels such asthe iliac (common, internal or external iliac arteries), superficialfemoral or popliteal arteries, medium-sized vessels such as the anteriorand posterior tibial arteries, or small vessels such as those of thepedal arch. While larger vessels are often amenable to invasiverevascularization with bypass surgery, angioplasty or stenting,infra-popliteal PAD is a particular challenge, as revascularizationoften fails. Vessels at the level of the pedal arch or below are oftentoo small to revascularize with current methods.

Once a diagnosis of that anatomic level of PAD is made, TUS wearabledevices such as sleeves, socks, or other form factors can be chosen tofocus energy on the area of interest. Not to be limited by theory, butultrasound such as SWT and TUS can provide at least two benefits: 1)collateralogenesis: promoting collateral vessel growth around areas ofmacrovascular obstruction as well as 2) angiogenesis: increasingcapillary formation and microvascular density and leading to greaterperfusion in distal muscle. Thus, for patients with PAD at the level ofthe femoral artery, a thigh sleeve may be applied to promote collateralvessel growth around stenoses, as well as a calf sleeve to increasemicrovascular density in the muscles of the calf. For example, patientswith infra-popliteal PAD, calf and ankle sleeves may be used forcollateralogenesis around the tibial arteries and pedal arch, andangiogenesis in the gastrocnemius and soleus muscle. Choice of specificsleeves/anatomic level may be left up to the clinician or prescribed viaan algorithm. For example, some methods using an anatomic approach aredescribed elsewhere herein. Suprapopliteal PAD can be treated with thighand/or calf wearable devices such as sleeves in some embodiments (e.g.,if not revascularized or previously revascularized and restenosed),while infrapopliteal PAD can be treated with calf and/or ankle orplantar foot sleeves in some embodiments (FIG. 8C). Some embodimentsalso provide for increased blood flow via nitric oxide-mediatedmechanisms and vasodilation (which is distinct from angiogenesis).

In some embodiments, ultrasound can be delivered non-invasively to apatient sufficient to, for example, increase distal perfusion due toincreased growth of collateral vessels around a macrovascularobstruction and/or increase in microvascular density (e.g., increasedcapillary density in a desired target location, such as thegastrocnemius).

Collateralogenesis and/or angiogenesis can potentially participate inthe effect of ultrasound, such as TUS on PAD. However, depending on thedistribution of PAD, TUS can be directed to specific parts of the lowerextremity to harness one or both of these mechanisms.

Patients with supra-popliteal PAD can have macrovascular blockagesaround the vessels in the thigh, claudication in the calf due toischemia in the gastrocnemius and soleus muscles, and may developchronic or critical limb ischemia (CLI) due to ischemia in the digits ofthe foot. However, some patients have isolated infra-popliteal PAD(which can be much less amenable to revascularization), or have theirsupra-popliteal PAD revascularized and are left with infrapopliteal PAD.These patients have macro-vascular obstruction in the tibial arteriesand pedal arch, and may also develop CLI.

Thus, ultrasound transducers may be selected and positioned particularlyto target specific angiosomes including one or more lower extremityarteries and their surrounding tissues as described above. In someembodiments, use of an ultrasonic thigh sleeve around the femoral arteryangiosome could promote collaterals around stenosis in the femoralartery, as well as angiogenesis in the quadriceps and/or hamstringmuscles. A posterior calf angiosome sleeve could promote collateralsaround the posterior tibia artery, and angiogenesis in the gastrocnemiusand soleus muscles, for example. With respect to infrapopliteal disease,a calf sleeve could promote collaterals around the posterior tibiaartery, while an ankle sleeve could promote collateralogenesis aroundstenoses in the pedal arch. FIGS. 5A-5C schematically illustratesembodiments of wearable ultrasound-based devices 500 including sleeve102 and transducer(s) 106 for placement over the outer surface of thefoot (not necessarily to scale) for treating PAD, sized and configuredfor placement around the thigh, calf, and midfoot respectively. In someembodiments, the sleeves and/or transducers can be configured to bemovable, such as in the direction of arrows, and also showingschematically non-limiting potential stop positions.

Also illustrated are various non-limiting arterial vessels that may beinvolved in PAD and treated using systems and methods disclosed herein(along with other anatomical landmarks) as shown in FIGS. 5D-5F, andhighlighted potential vessels that can be treated in a wearable footdevice, such as a sock (FIG. 5F).

In some embodiments, systems and methods can be configured forangiosome-specific positioning of the device to position major vesselsand muscles in the near-field and bone in the far-field (with specificanatomic markers on the device to guide placement), e.g., about the 3o′clock position on the medial thigh; 6 o′clock on the posterior calf,and 12 o′clock position on the plantar mid-foot wherein 12 o′clock isgenerally the anterior surface of the leg and foot (e.g., the patient’sshin).

In some embodiments, a larger sleeve may be developed to target two orthree lower extremity segments, including a separate single-elementtransducer or separate array for each of the two to three segments: atwo-element sleeve for thigh and calf; a two-element “boot” for calf andmidfoot; a three-element sleeve for thigh, calf and midfoot.

Depending on transducer size and design, the entire segment of thigh,calf, ankle, or plantar foot may not be able to be treated with thetransducer in one location. Furthermore, maintaining the transducer andcoupling gel or gel pack at the same skin location may predispose toinfection, contact dermatitis, or simply discomfort. While the sleeveitself may be repositioned longitudinally along the lower extremitysegment, to allow reliable movement of the transducer longitudinallyalong the sleeve. Additionally, clear numbering allows for prescriptionof TUS treatments by the medical provider along a given segment. In someembodiments, the ultrasonic gel or other media is self-contained withina closed pack or other housing and as such the gel or other media doesnot directly contact the skin surface of the patient. As such, in someembodiments, a patient advantageously may have more freedom of movementwithout concern that the gel or other media will spill out when thepatient raises their extremity or changes position.

As illustrated in FIGS. 6A-6B, a coupling gel (or adhesive gel pack) canbe disposed between the transducer and the skin surface. FIG. 6Aillustrates a schematic cross-sectional view of a wearableultrasound-based device including a sleeve 102, and a transducer 106positioned between the sleeve 102 and the skin surface 601. FIG. 6Billustrates an ultrasound gel pack 602 positioned in between theultrasound transducer 106 and the sleeve 102, according to someembodiments of the invention. The coupling gel could be, for example, awater or other media-based acoustically inert ultrasound gel manuallyapplied to area of skin underneath the transducer. The gel could also beincluded in a pack (housing) filled with ultrasound gel shaped toconform to transducer surface. The pack could be, for example, adhesiveon the skin side, transducer side, neither or both. The gel pack couldbe disposable, such as on a daily or weekly basis. Alternatively, awater-filled inner sleeve 604 positioned radially inward to the sleeve102 and transducer 106 could be used for both coupling and cooling, asillustrated in FIG. 6C.

In some embodiments, the transducer surface can be coated with amaterial to prevent corrosion from frequent exposure to ultrasound geland/or adhesive material of gel pack.

In some embodiments, the ultrasound-based device can be configured forup to three times daily or more frequency of use, elements of the deviceneed to be disposable and/or washable to prevent infection. The sleevecan be washable (or single-use disposable in some cases), and theadhesive gel pack may be reusable or disposable as well.

FIG. 7 schematically illustrates two embodiments of the wearableultrasound sleeve displayed in unwrapped form. In some embodiments, awearable device, such as a sleeve can includes one or more positioningguides such as indicia, to aid the patient in appropriately positioningthe transducers. In some embodiments, an “anterior” or “posterior”reference line(s) is/are drawn on the sleeve to aid patient inpositioning sleeve such that transducer faces appropriate lowerextremity surface. FIG. 7A schematically illustrates a wearableultrasound sleeve 700, including an indicia of positioning, positioningguides, a transducer dock 710, and battery dock 720. For a calf sleevefor example, the indicia of positioning cranio-caudally can be locatedanteriorly (e.g., an axially-extending positioning line with arrows730), while the transducer dock can be located posteriorly, althoughother positions are possible as described elsewhere herein. Avertically-oriented line 730 can be printed with cranial “head” andcaudal “foot” orientation arrows on the sleeve or other indicia as shownin some embodiments. The patient can be instructed to orient this linewith the front of the thigh (for a thigh sleeve), front of the shin/knee(for a calf sleeve), and back of the ankle (for an ankle sleeve), forexample. The transducer docks can be positioned at an appropriatedistance from this line based on average human leg circumferences suchthat the transducer is aimed at the appropriate lower extremity surfaceor other target location. Positioning over landmarks such as the calfborders or the popliteal fossa could ensure consistent muscle and arterycoverage.

In some embodiments, a longitudinal transducer “dock” is incorporatedinto sleeve design with several numbered locations at each site that thetransducer can be secured longitudinally along the sleeve as shown inFIG. 7A. For indications such as PAD, the length of the desiredtreatment area within a lower extremity segment could potentially belonger than the length of a single transducer. Furthermore, maintainingthe transducer and coupling gel or gel pack at the same skin locationmay predispose to infection, contact dermatitis, or simply discomfort.For example, the gastrocnemius/soleus and length of posterior tibialartery may be longer than a transducer within a calf sleeve; or thelength of femoral artery to be treated for a thigh sleeve. In someembodiments, a longitudinal transducer dock can allow for repositioningof an ultrasound transducer cranio-caudally along a given segment. Inother words, positional guides on the transducer dock allow the patientto vary position of the single element or array of transducers betweentreatments while maintaining similar sleeve position. For example, thepatient may be instructed to place the transducer at a first reversiblydetachable dock site for a first treatment, and a second reversiblyattachable dock site for a second treatment. The dock site could be, forexample, a snap-fit dock, hook-and-loop fastener material, or anotherconnector. In some embodiments, multiple ultrasound transducers can beconnected to a single device, such as a sleeve and to a single powersource. The transducers can be aligned axially in series,circumferentially, or other configurations depending on the desiredclinical result. The sleeve itself may be repositioned longitudinallyalong the lower extremity segment, to allow movement of the transducerlongitudinally along the sleeve. Additionally, clear numbering allowsfor prescription of TUS treatments by the medical provider along a givensegment, such as longitudinally or axially along the sleeve. In someembodiments, the device can be configured to direct ultrasonic energy toone or more of the thigh, calf, and/or foot either serially or inparallel.

FIG. 7B demonstrates an embodiment of a sleeve 700 with an 8-transducerarray 707, positioning line 730, and battery/interface 720. In someembodiments for a calf sleeve for example, the positioning line 730could be between about 20 cm and about 40 cm in length, such as about 30cm, and the transducers could have a diameter of between about 1 cm andabout 10 cm, or about 6 cm or other values as described elsewhereherein.

In some embodiments, an ankle transducer may be incorporated as part ofa “boot” that fits around the entire foot, maintaining the transducer indesired anterior position and also containing the battery/generator packwith no exposed wiring. Similarly a foot transducer may be incorporatedas part of a “sock” that fits around the foot and with transducersfacing the plantar foot surface. In some embodiments, the sock could beclosed or open toes, that is have either closed or open distal endsdepending on the desired clinical result.

SWT, by definition, provides only one pressure wave in each pulse,limiting the negative pressure pulses that may lead to angiogenesis viacavitation or shear stress. TUS provides multiple pressure waves in eachpulse, potentially allowing for more frequent delivery of negativepressure pulses, as illustrated schematically in FIG. 3 discussed above.TUS may increase tissue VEGF levels compared with SWT and sham therapy.TUS and SWT can also increase gastrocnemius microvascular density, andalso improve distal perfusion. Longer TUS treatments with or withoutfurther titration of TUS parameters can further increase thesesynergistic effects in some embodiments.

It is advantageous that the ultrasound delivered be well-tolerated bythe patient. However, at certain parameters, it is possible that TUS maycause pain, discomfort, or nerve stimulation. Some TUS parameters thatcould result in these symptoms are p⁻/MI and pulse duration/duty cycle,among others. In some embodiments, these parameters are controlled tostay below, such as just below the pain/nerve stimulation threshold andimprove tolerance and compliance, and increase clinical effects. Theparameters in some embodiments can be adjusted manually by thehealthcare provider and/or the patient, such as via a user control onthe device or a wired or wireless remote, such as a tablet orsmartphone, for example.

Acoustic waves may be distorted by air in the interface between thetransducer and the skin, reducing delivery of TUS energy to tissue,and/or resulting in transducer heating (due to reflection back to thetransducer). As such, stable air-free contact between the transducer andthe skin can be advantageous in some cases.

In some embodiments, the ultrasound-based wearable device includes aportable battery; connection to an external power source can be highrisk in some cases and uncomfortable for nighttime use. A portable,detachable and rechargeable battery (with incorporated generator) can beconnected to transducer, and also fixed into position within the sleeve.During times of non-use, the battery can be disconnected from thetransducer, removed from sleeve, and connected to a charging station.Battery capacitance/voltage design can be sufficient in some cases topower a device for > 8 hour use or other appropriate time period ataforementioned ultrasound parameters. However, other embodiments caninclude wired AC power connections.

FIGS. 8A-8C illustrates non-limiting positions of an ultrasoundtransducer adjacent the skin surface of an anatomical target location.FIG. 8 illustrates non-limiting positions of an ultrasound transduceradjacent the skin surface of an anatomical target location. In FIG. 8A,the transducer (or array) is illustrated positioned along the medialaspect of the thigh, maintaining the femoral artery in the acousticnear-field and femur in far-field so as to maximize vascular exposureand minimize bone exposure of acoustic tissue. In FIG. 8B, thetransducer (or array) is positioned over the posterior aspect of thecalf, maintaining the gastrocnemius, soleus, and posterior tibial arteryin the near-field, and tibia and fibula in far-field. In FIG. 8C, thetransducer (or array) is positioned over the plantar mid-foot,maintaining the plantar arterial arch in the near-field and metatarsalsin the far-field. Positioning of the transducers/sleeve can bedetermined by the health care provider depending on the desired clinicalresult. In the thigh, the superficial femoral artery is positionedanterior at the level of its bifurcation off of the common femoralartery, moves to the medial part of the thigh as it descends caudally,and rotates posteriorly where it becomes the popliteal artery. Thus, insome embodiments, to advantageously promote collateralogenesis aroundobstructions in the SFA, the transducer can be positioned along themedial aspect of the thigh. In some embodiments, the transducer can alsobe positioned along the anterior, posterior, or lateral aspects of thethigh. FIG. 8D schematically illustrate additional vessels on the dorsaland plantar surfaces of the foot that can be treated using systems andmethods as disclosed herein.

In the calf, the popliteal artery divides to become the anterior andposterior tibial arteries. The tibia is prominently situated along theanterior portion of the infrapopliteal lower extremity, and bonereflects and distorts acoustic energy. While the transducer can bepositioned anteriorly, medially, or laterally, positioning thetransducer along the posterior aspect of the calf can advantageouslyallow for increased angiogenesis to increase microvascular density inthe gastrocnemius and soleus muscles, and/or collateralogenesis aroundthe posterior tibial artery with minimal acoustic distortion by thetibia and fibula.

In the ankle, the dorsalis pedis artery and the pedal arch run on theanterior surface of the ankle. Positioning of the transducer over theanterior surface can advantageously promote collateralogenesis aroundPAD in these small vessels. Furthermore, the anterior surface of theankle is relatively flat compared to the posterior surface, allowing formore secure positioning of the transducer and gel pack. However, in someembodiments, the transducer can be positioned along the medial, lateral,or posterior surface of the ankle. The transducer can also be positionedunderneath the foot to target the muscles of the feet and promoteangiogenesis, such as in the sole of a shoe or shoe insert for example.

In the foot, the plantar arch continues from the posterior tibial arteryand bifurcates into the lateral and medial plantar arteries. The plantarfoot also include several layers of muscles, and is relatively arched ina concave shape. Positioning of the transducer on or proximate theplantar surface of the foot can simultaneously promotecollateralogenesis around blockages in the plantar arch arteries andpromote angiogenesis in the muscles of the feet.

Particularly with prolonged nighttime use (up to 12 hours), at higheracoustic intensities (p-, Ispta), and longer duty cycles (>10%), heatingof the transducer and skin may occur. Typically, FDA requirementsrequire a thermal index < 6.0, and a probe surface not to exceed 43° C.in contact with skin, and 50° C. in air. Incomplete seal with ultrasoundgel or the adhesive gel pack, resulting in significant air bubbles inthe acoustic field may increase heating. Thus, safety mechanisms can bebeneficial to prevent thermal skin damage. In some embodiments, athermocouple may be integrated onto the transducer surface with afeedback loop to the battery/generator to turn off the device uponsensing a temperature greater than a predetermined threshold limit(e.g., greater than about 40° C., 41° C., 42° C., 43° C., or more orless in some embodiments). In some embodiments, the system including thetransducer (or transducer array) can include a cooling system to preventoverheating and temperature control and be cooled via a fluid, such asin a closed fluid loop that circulates around the transducer, removingheat. In some embodiments, the transducer is air-cooled via one or morefans. In some embodiments, ultrasound gels with large heat capacitancecan be utilized. The gels could include, for example, a conformable,high heat-capacity matrix with embedded thermal capacitors comprisingphase change materials (PCMs) or other endothermic materials. In someembodiments, the thermal conductivity of the PCMs or the gel itself maybe enhanced through the addition of high thermal conductivity particles.These particles can include materials such as, for example and notlimitation, thermally conducting polymers, metallic nano or microparticles, carbon based materials, or other high thermal conductivitymaterials. In some embodiments, the sleeve can include cut-out windows,or be made of a breathable material for air cooling of the transducer.An adhesive coupling gel pack between the transducer and skin can alsohelp to dissipate transducer heat by conduction, and limit heating ofskin.

In another embodiment of the device, adequate and gasless coupling ofthe transducer/array to skin can be monitored by real-time, in-treatmentassessment of reflected acoustic power back at the transducer. Highreflected power (e.g., about or at least about 5%, 6%, 7%, 8%, 9%, 10%,11%, 12%, 13%, 14%, 15%, or more of the forward power delivered by thegenerator) can be indicative of air in the transducer-skin interface,and the system can be programmed to automatically stop energy deliveryin such cases.

Positioning of the sleeve and transducer/array may be varied to optimizethe effects of collateralogenesis and angiogenesis by placing arteriesand muscle in the acoustic near-field, and minimize acousticreflection/scattering by maintaining bone in the far-field, as shownschematically in FIGS. 8A-8C. In one embodiment at the level of thethigh, the transducer or array could be positioned medially, maintainingthe femoral artery in the acoustic near-field and femur in the far-field(FIG. 8A). In the calf embodiment, the transducer or array could bepositioned posteriorly, maintaining the gastrocnemius, soleus, andposterior tibial artery in the near-field, and tibia and fibula in thefar-field. In the mid-foot embodiment, the transducer/array could bepositioned over the plantar surface, maintaining the plantar arterialarch in the near-field and metatarsals in the far-field (FIG. 8C).

Bone, implants (e.g., titanium implants), external braces or solidmatter or other hardware, or other highly echogenic material in thenear-field of the transducer can be undesirable in certain embodiments,and may lead to acoustic reflection, scattering, and may increase riskof transducer heating or other adverse events. Thus, in anotherembodiment, the device may include one or more ultrasound ornon-ultrasound (e.g., photo or video based, such as a CCD, CMOS, orother camera configured to identify the target anatomy, X-ray, CT, or MRbased) imaging components (e.g., ultrasonic sensors or software/imageprocessing quantification of echogenicity) to assess for echogenic boneor air in the near-field. This may be incorporated into the therapytransducers themselves (A-mode imaging), or with a separate imagingtransducer (M-mode or B-mode imaging). When not applying therapeuticultrasound for example, the therapy transducers in diagnostic mode orthe separate diagnostic imaging transducers can send diagnosticultrasonic energy (e.g., in pulses) to measure reflected acoustic power.In other words, the system can include dual diagnostic imaging andtherapeutic imaging functions in some embodiments. In some embodiments,the diagnostic imaging modality can be utilized to locate and identifythe particular anatomy to be treated (e.g., with anatomical landmarksidentifiable by the device). As such, in some embodiments systems andmethods can advantageously direct and preferentially direct therapeuticenergy to target tissue, e.g., the angiosomes with the energy therapylisted elsewhere herein, targeting an artery and the tissue around theartery, and minimize energy delivery to bone or other solid/relativelymore echogenic tissues.

In some embodiments, the reflected acoustic energy can be sensed as avoltage from the transducer. A pre-specified upper voltage limit can beset based on known normal parameters for correct device positioning. Ifreflected voltage is sensed to be above this upper threshold, this willsuggest echogenic bone or air in the near-field is detected, and thecontroller can deactivate the transducer(s) and indicate to the userthat the device needs to be repositioned. In some embodiments that usean array of transducers, acoustic energy can selectively be turned offonly to the transducer(s) that detect high reflected acoustic power,allowing the remainder of the array to continue providing therapeuticenergy delivery. In some embodiments, bone or other undesired materialcan be identified by the system based on differential acousticreflectivity, for example the system can identify bone as apredetermined, e.g., about 1.5x, 1.75x, 2x, 2.25x, 2.5x, 2.75x, 3x, ormore greater than background or average, reflectivity, and energy can bedirected to the near field away from the bone or other undesiredmaterial.

In some embodiments, a patient-driven method of placement can beutilized by using a “PUSH” technique-Place Until Softness Heard. Assuch, ultrasound intensity can be converted (such as from reflectiveacoustic pressure/voltage into audible sound), or other indicia. Theindicia could be, for example, a visual signal (e.g., a change inbrightness or color change on an LED light or display), or aquantitative score on a display; or tactile feedback such as differentdegrees of vibration for example, so long as the patient or provider canobtain feedback that device is positioned over soft tissues (e.g.muscle, arteries which would be quiet) rather than hard tissues (e.g.bone which would give a loud signal). In some embodiments, the signalcould be binary - e.g., a warning beep or other alarm if the device isplaced over hard tissues, and no sound or a confirmatory pleasant tone,etc. if the device is placed over soft tissues.

It could be useful in some cases to detect measures of blood flow andperfusion on the same platform/system that delivers the acoustic energy,or a different system. Light-based sensors that detect scattering (e.g.,diffusion correlation spectroscopy or diffuse speckle contrast analysistechniques) or absorption as a function of hemoglobin concentrations incirculating blood can be incorporated. Thus, in another embodiment, alight-emitting diode and sensor can be placed in the ultrasound field,or proximal or distal to the site of ultrasound application, todetermine acute (within minutes or hours) or chronic (within days orweeks) changes in perfusion as a sign of response and success oftherapy. In some embodiments, angiogenesis, collateralogenesis anddirect or indirect improvements in perfusion may be assessed andquantitated by perfusion-specific magnetic resonance imaging, laserDoppler imaging, angiography (including CT, MR, and intra-arterialcatheter angiography, and fluorescence microangiography), systematiculcer/wound assessment, microbubble ultrasound perfusion imaging,ankle-brachial index, toe-brachial index or transcutaneous oximetry(TcPO₂)″

Carotid, renal, and other arteries may be stenosed/obstructed inpatients with or without PAD. In addition to the lower extremities, PADpatients often have atherosclerosis in the carotid arteries, placingthem at risk for stroke and hypertension/renal injury, respectively. Aswith lower extremity PAD, treatment of two disease processes istypically also limited to medical therapy, and catheter-based orsurgical revascularization, all of which have their limitations.

In some embodiments, an ultrasound-based device is sized and configuredto fit around the neck of a patient with a transducer on a desiredlocation, e.g., unilateral or bilateral carotid arteries. The devicecould take the form of a collar, for example. The device could include acircular transducer, with a spherical curvature in some embodiments. Thediameter of the transducer could be, for example, between about 1 cm andabout 5 cm, such as between about 1 cm and about 2 cm, between about 2cm and about 4 cm, and or between about 3 cm and about 5 cm. Thetransducer could have a radius of curvature, for example, of betweenabout 0 cm and about 50 cm. In some embodiments, the transducer could berectangular with a cylindrical curvature. The height of the transducercould be, for example, between about 1 cm and about 5 cm, such asbetween about 1 cm and about 2 cm, between about 2 cm and about 4 cm, orbetween about 3 cm and about 5 cm. The radius of curvature of thetransducer could be, for example, between about 0 cm and about 100 cm.The width of the curvature could be, for example, between about 1 cm andabout 5 cm, such as between about 1 cm and about 2 cm, between about 2cm and about 4 cm, or between about 3 cm and about 5 cm.

In some embodiments, an ultrasound-based device is sized and configuredto fit around the torso, back, or abdomen with the transducer positionedover one or both renal arteries. The device could include a circulartransducer, with a spherical curvature in some embodiments. The diameterof the transducer could be, for example, between about 10 cm and about30 cm, such as between about 10 cm and about 20 cm, between about 15 cmand about 25 cm, and or between about 20 cm and about 30 cm. Thetransducer could have a radius of curvature, for example, of betweenabout 0 cm and about 300 cm. In some embodiments, the transducer couldbe rectangular with a cylindrical curvature. The height of thetransducer could be, for example, between about 10 cm and about 30 cm,such as between about 10 cm and about 20 cm, between about 15 cm andabout 25 cm, or between about 20 cm and about 30 cm. The radius ofcurvature of the transducer could be, for example, between about 0 cmand about 300 cm. The width of the curvature could be, for example,between about 10 cm and about 20 cm, such as between about 10 cm andabout 15 cm, between about 15 cm and about 20 cm, between about 12 cmand about 15 cm, or between about 15 cm and about 18 cm.

In some embodiments, the wearable device could take the form of,include, or only include, for example, a vest (for the chest), armband(for the upper extremities), glove (for the hands), boot (for theankle), sock (for the feet), a cup or undergarment (for vascularerectile dysfunction), decal/sticker (e.g., self-adhesive), abdominal orback brace/binder (e.g., for renal or abdominal indications for example)or other form factor depending on the desired clinical result.

FIG. 9 illustrates an embodiment of a single-element transducer 900having a circular geometry with a spherical curve (on the left), as wellas a transducer 901 with a rectangular geometry with a cylindrical curve(on the right). The transducer could in some embodiments include a taperwith multiple radii of curvature including first radii of curvature (a)and second radii of curvatures (b) as illustrated in the right-handembodiment.

Unlike FIG. 9 , which illustrates embodiments of spherical andcylindrically focused transducers which are concave, and thus conform tothe curvature of the lower extremity, other embodiments may contain aconvex transducer in which the acoustic field becomes wider than thecross-sectional area of the transducer. This may require higher power toachieve equivalent acoustic pressures at depth, but allows for treatmentof a larger area of tissue with a transducer of equivalentcross-sectional area.

Other non-convex designs, for example with multiple transducers orientedat varying radial directions of focus within a flat array oftransducers, may also achieve a divergent or spreading ultrasound beamfor maximum muscle and vascular target coverage with minimal transducersize.

In some embodiments, the transducer can be configured to conform to thecurvature of lower extremity for optimal improved and wearability. Boththe transducer and battery/generator may be gently curved to conform tothe curvature of the thigh, calf, or ankle. Fixed curvature transducersmay be fabricated based on average human lower extremity curvatures. Thecurvature could be, for example, spherical or cylindrical, and have asingle multiple radii of curvature along the length to best conform toanatomy. This can advantageously minimize device bulk, increase comfort,and (in the case of the transducer), limit the volume of coupling gel orgel pack and minimize risk of air incorporation into transducer/tissueinterface. In some embodiments, the system can include a single deviceincorporating a removable/rechargeable power supply, transducer array,and sleeve can conform to thigh, calf, or foot. Alternatively, in otherembodiments, one device for the entire lower extremity can treat all ofthe angiosomes from thigh to foot, or calf to foot.

In some embodiments, flexible piezoelectric materials may be used toallow alteration of transducer shape to fit patient’s lower extremitysegment. Flexible and stretchable electronic materials exist which maycontain piezoelectric materials and be much thinner than conventionalpiezoelectric materials. Some examples of composite piezoelectricmaterials can take the form of pastes or paints in the form of soft ormalleable materials. These materials are also referred to aspiezoelectric thick film materials or piezoelectric paint. Suchmaterials can be integrated, for example, in a band-aid design and thusadhered to the patient’s anatomy.

Phased array element transducer embodiments may contain arrays ofmultiple transducers (e.g., 2, 4, 6, 8, 10, 12, 16, 24, 32, 64, 128,256, 512) or more, or ranges including any two of the foregoing values)operating with one, some, or all out of phase with each other. Eachelement of the array may be flat circular, oval, spherical, cylindrical,rectangular, or other shapes. The surface area of each transducerelement may be, in some embodiments between about 2 cm² and about 100cm². Circular elements, for example, may have diameters between about 1cm and about 20 cm, such as about 4 cm, about 6 cm, or about 9 cm insome embodiments. The individual array elements may be arranged within atransducer housing having non-limiting shapes (such as rhombus, oval,trapezoidal) to specifically conform to the anatomic treatment area.Each transducer in the array can be arranged such that the array issymmetric or asymmetric along one, two, or more axes. Each element ofthe array may be affixed to the inner surface of the sleeve with amagnetic, button-based, Velcro or glue-based mechanism. Each element canbe wired to the battery/generator/interface console to allow programmingfor phased pulsed therapy. Embodiments with single element transducerscan be fabricated with multiple different curvatures and sizes toaccount anatomic variations. As noted above, in some embodiments,polygons with short axes substantially parallel to the direction ofcurvature can be used to advantageously allow forconformability/flexibility while maintaining maximal surface areacoverage, for example a diamond with the short axis oriented to thedirection of curvature around the calf or foot. Array-based embodimentscan allow the sleeve to more readily “wrap” around human extremities ofvarious sizes, with the array elements conforming to the desiredanatomic shape. Certain embodiments of the array-based device can allowindividual array elements/transducers to be temporarily inactivated bythe user or the system if they are outside the desired anatomictreatment area. The remaining elements that are placed properly over theanatomic therapeutic area can still provide the desired energy delivery.

FIGS. 10A-10F illustrates arrays of transducers in a polygonal shape,connected with a wearable component, such as a sleeve, and in some casescan include a meshwork to allow flexible coverage of a body part, forexample, the calf surface from the popliteal fossa to the Achillestendon, or for example plantar foot surface from the calcaneus to themetatarsal-phalangeal joint. Specific array shapes may be chosen tomatch a given patient’s anatomy and the desired clinical result, as wellas to optimize both desired packing densities and enhanced flexibility.Furthermore, in certain embodiments, the mesh sleeve may be made to bereadily altered such that the array shape can be chosen and designed bythe user to match patient anatomy. In other embodiments, polygons withshort axes substantially parallel to the direction of curvature can beused to advantageously allow for conformability/flexibility whilemaintaining maximal surface area coverage, for example a diamond withthe short axis oriented to the direction of curvature around the calf orfoot.

In some embodiments, each transducer could have a duty cycle that is upto 1/(total number of transducers), for example in an array of 8transducers, each may have up to a 12.5% duty cycle. FIGS. 10A-Bdemonstrate two shapes of arrays 1002 of 16 circular transducers 1000(e.g., about 4 cm in diameter in some embodiments) (FIG. 10A being atrapezoidal shape, and 10B being a diamond or truncated diamond shape).FIGS. 10C-D demonstrate two shapes of arrays of 8 circular, (e.g., about6 cm in diameter in some embodiments) transducers (FIG. 10C being atrapezoidal shape, and FIG. 10D being a diamond or truncated diamondshape). FIGS. 10E-F demonstrate two shapes of arrays of 4 circular,(e.g., about 9 cm in diameter in some embodiments) transducers (withFIG. 10E being a trapezoidal shape and FIG. 10F being a diamond ortruncated diamond shape). Other shapes are possible as noted elsewhereherein. Table 1 below compares non-limiting examples of embodiments ofthe surface area of each transducer and each array.

TABLE 1 Design # transducers Transducer diameter (cm) Transducer SA(cm²) Total SA (cm²) A 16 4 12.56636 201.06176 B 16 4 12.56536 201.06176C 8 6 28.27431 226.19448 D 8 6 28.27431 226.19448 E 4 9 63.6171975254.46879 F 4 9 63.6171975 254.46879

Each transducer element in an array can be spaced sufficiently apart soas to avoid acoustic interaction of side lobe artifacts emanating fromone transducer with adjacent transducers. The width of side lobes may bemeasured prior to array fabrication, and elements can thus be spacedaccordingly.

In some embodiments, the adjacent transducers are driven entirely inphase. In some embodiments, adjacent transducers are driven out of phasewith each other, such as about 90, 180, or 270 degrees out of phase witheach other.

FIG. 11 illustrates non-limiting embodiments of a matrix of anatomiclocations of transducer/array placement to optimize macrovascularcollateralogenesis and microvascular angiogenesis (cross-hatched) bymaintaining arteries and muscles in the acoustic near-field, and tominimize acoustic reflection (diagonal line shading) by maintaining bonein the far-field.

In some embodiments, systems and methods as disclosed herein can treator prevent PAD, renal artery stenosis, carotid stenosis,vertebro-basilar insufficiency, brachial stenosis, axillary stenosis, oratherosclerosis or stenosis or other disease of any other vessel(including those described and/or illustrated herein) or body structure,and related vascular diseases such as atrial fibrillation or otherarrhythmias, congestive heart failure (including ischemiccardiomyopathy). In some embodiments, systems and methods can be used totreat Alzheimer’s or vascular dementia, and/or TIAs or ischemic stroke(e.g., with a ultrasound-based external cap or a catheter-basedintravascular device for example).

The pathophysiology of diabetic foot ulcers is multifactorial, but, inpart, are due to micro- and macro-vascular ischemia. Embodiments of thisdevice may also be used for the clinical application of diabetic ulcerhealing.

Other embodiments may be used to treat acute limb ischemia,hypoperfusion due to trauma and/or restless leg syndrome, which can havepathophysiologic mechanisms of vascular dysfunction and ischemia.

By treatment is meant at least an amelioration of the symptomsassociated with the pathological condition afflicting the host, whereamelioration is used in a broad sense to refer to at least a reductionin the magnitude of a parameter, e.g. symptom, associated with thepathological condition being treated, such as ischemia. As such,treatment includes situations where the pathological condition, or atleast symptoms associated therewith, are completely inhibited, e.g.prevented from happening, or stopped, e.g., terminated, such that thehost no longer suffers from the pathological condition, or at least thesymptoms that characterize the pathological condition. For example,treatment of PAD can result in reduction of claudication includingrest-induced ischemic pain and/or exercise-induced ischemic pain,improvement in the ankle-brachial or toe-brachial index or othermeasurement of perfusion (including radiographic), transcutaneous oxygenpressures, duplex peak systolic velocity or velocity ratios, ankle ortoe pressures, healing of ulcers, infections, or other wounds,prevention of gangrene, or other parameters. Systems and methods canalso be used to treat ischemic injury as a result of trauma, battlefieldinjury, compartment syndrome, or even to enhance angiogenesis oftissues, organs, or even limbs after surgery or transplantation. In someembodiments, systems and methods as disclosed herein can be used totreat deep venous thrombosis (DVTs) and create venous vessel growth inthe arms and legs, such as with a wearable device as described elsewhereherein. Systems and methods could also potentially be utilized to treatpulmonary embolism or pulmonary hypertension (e.g., with a thoracic vesttargeting the lungs, pulmonary arteries, pulmonary veins, and/orbronchial arteries for example) to aid angiogenesis directed toward thelung vasculature, and/or offloading strain of the right heart. In someembodiments, systems and methods as disclosed herein can be utilized totreat or prevent preeclampsia or eclampsia by focusing therapeuticenergy toward the placenta using parameters as described herein. Not tobe limited by theory, while not well understood, preeclampsia andeclampsia can be associated with poorly developed uterine placentalspiral arterioles (which decrease uteroplacental blood flow during latepregnancy), a genetic abnormality on chromosome 13, immunologicabnormalities, and placental ischemia or infarction. Diffuse ormultifocal vasospasm in the placenta can result in maternal ischemia,eventually damaging multiple organs, particularly the brain, kidneys,and liver. Factors that may contribute to vasospasm include decreasedprostacyclin (an endothelium-derived vasodilator), increased endothelin(an endothelium-derived vasoconstrictor), and increased soluble Flt-1 (acirculating receptor for vascular endothelial growth factor). Systemsand methods (e.g., an abdominal binder, sleeve, or other wearable orother form factor) can preferentially cause promote placentalangiogenesis thereby preventing or reversing the pathophysiology ofplacental vascular insufficiency in disorders such as pre-eclampsia andeclampsia. Treatment or prevention of ulcers may also be used fordiabetic foot ulcers, with or without concomitant PAD, with similarwearable ultrasound methods and systems inducing angiogenesis. Treatmentof renal artery stenosis, acute or chronic renal failure (e.g., withangiogenesis to one or both kidneys) can manifest as improved BUN,creatinine, GFR, blood pressure, plasma renin, angiotensinogen,angiotensin I, angiotensin II, ACE, or other parameters. Treatment ofcarotid artery stenosis can manifest as reduced transient ischemicattacks (TIA) or stroke. In some embodiments, the system can alsoinclude a diagnostic component for measuring perfusion at the anatomicallocation being treated, including a Doppler ultrasound perfusionmeasuring device or an optical perfusion measuring device, e.g., diffusecorrelation spectroscopy or diffuse speckle contrast analysis in orderto provide qualitative and/or quantitative measures of blood flow priorto, during, and/or after treatment sessions, which can be output to adisplay (in real-time in some cases). In some embodiments, the perfusionor other data can be utilized as a closed-loop feedback parameter tocontrol or adjust therapy. In some embodiments and not to be limited bytheory, Doppler or other blood flow measurements can be used to detectvasodilation using the same transducer or array, and use an acute bloodflow increase above a predetermined threshold (e.g. about or at leastabout 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or more) as aproxy for ultimate angiogeneic effects. Above parameters (peak negativepressure, frequency, continuous or pulsed wave, duration, etc. can bethus customized/personalized to dial-in tailored acoustic parameters fora given patient and anatomic site, since local factors (obesity,hydration, skin thickness, etc.) can potentially affect optimalacoustics (e.g., SONAR--Sound Optimizing dilatioN for AngiogenicResponse). In some embodiments, systems and methods as disclosed hereincan also treat venous insufficiency (e.g., via venous collateralformation), acute or chronic pain, neuropathies, rheumatoid orosteoarthritis, cellulitis, osteomyelitis, or chronic wounds, Raynaud’sor other vasospastic diseases, peripheral edema including venous stasisand lymphedema, erectile dysfunction in both males and females (e.g.,via focused ultrasound to the, e.g., pudendal or clitoral artery),ischemic bowel (e.g., via focused ultrasound to arteries/tissue of theGI tract), or a variety of other indications. In some embodimentssystems and methods as disclosed herein can be part of a combinationtherapy to achieve an unexpectedly synergistic result. In someembodiments, ultrasound systems and methods as disclosed herein could becombined with pharmacologic therapy including antiplatelet therapy suchas aspirin or clopidogrel, or anticoagulation therapy such as warfarin,heparin, low-molecular weight heparin, dabigatran, rivaroxaban,apixaban, edoxaban, or other agents such as cilostazol andpentoxifylline, or thrombolytics including tPA, streptokinase,urokinase, and others. In some embodiments, systems and methodsdisclosed herein can treat or prevent restless legs syndrome, which mayhave a vascular ischemic component as noted above and thus responds todopaminergic pharmacotherapy, which can promote vasodilation.

In some embodiments, systems and methods could include a combination ofany number of the following modalities (in addition to, or as analternative to one or more ultrasound transducers) to achieve anunexpectedly synergistic benefit: light energy (e.g., via a laser),magnetic energy such as trans-cranial magnetic stimulation,radiofrequency energy, microwave energy, mechanical energy (e.g.,vibration or compression), electrical stimulation, thermal energy (e.g.,warming), cooling, hypoxia or hyperoxia, or localized drug delivery. Insome embodiments, systems and methods can be used to avoid aninterventional procedure such as a bypass procedure, angioplasty, orstenting, or to reduce the risk of restenosis or recurrent ischemiafollowing such procedures.

Various other modifications, adaptations, and alternative designs are ofcourse possible in light of the above teachings. Therefore, it should beunderstood at this time that within the scope of the appended claims theinvention may be practiced otherwise than as specifically describedherein. It is contemplated that various combinations or subcombinationsof the specific features and aspects of the embodiments disclosed abovemay be made and still fall within one or more of the inventions.Further, the disclosure herein of any particular feature, aspect,method, property, characteristic, quality, attribute, element, or thelike in connection with an embodiment can be used in all otherembodiments set forth herein. Accordingly, it should be understood thatvarious features and aspects of the disclosed embodiments can becombined with or substituted for one another in order to form varyingmodes of the disclosed inventions. Thus, it is intended that the scopeof the present inventions herein disclosed should not be limited by theparticular disclosed embodiments described above. Moreover, while theinvention is susceptible to various modifications, and alternativeforms, specific examples thereof have been shown in the drawings and areherein described in detail. It should be understood, however, that theinvention is not to be limited to the particular forms or methodsdisclosed, but to the contrary, the invention is to cover allmodifications, equivalents, and alternatives falling within the spiritand scope of the various embodiments described and the appended claims.Any methods disclosed herein need not be performed in the order recited.The methods disclosed herein include certain actions taken by apractitioner; however, they can also include any third-party instructionof those actions, either expressly or by implication. For example,actions such as “positioning a wearable ultrasonic sleeve on a patient’slower extremity” includes “instructing the positioning of a wearableultrasonic sleeve on a patient’s lower extremity.” The ranges disclosedherein also encompass any and all overlap, sub-ranges, and combinationsthereof. Language such as “up to,” “at least,” “greater than,” “lessthan,” “between,” and the like includes the number recited. Numberspreceded by a term such as “approximately”, “about”, and “substantially”as used herein include the recited numbers (e.g., about 10% = 10%), andalso represent an amount close to the stated amount that still performsa desired function or achieves a desired result. For example, the terms“approximately”, “about”, and “substantially” may refer to an amountthat is within less than 10% of, within less than 5% of, within lessthan 1% of, within less than 0.1% of, and within less than 0.01% of thestated amount.

What is claimed is:
 1. A method of treating peripheral vascular diseaseby stimulating angiogenesis within a patient, comprising: providing awearable non-invasive device comprising a flexible housing material andan array of ultrasound transducers operably attached to the flexiblehousing material; positioning the device and the array of transducersproximate a skin surface of a patient above at least one target siteangiosome below the knee where angiogenesis is desired, and such thatthe flexible housing material and the array of ultrasound transducerssubstantially conforms to the skin surface of one or more of the calf,ankle, and foot of the patient; and causing a therapeutically effectiveamount of ultrasonic energy having a surface intensity:depth ratio ofbetween about 0.10 W/cm³ and about 0.60 W/cm³ over a set time period tobe directed toward the target site angiosome, thereby stimulatingcavitation and shear stress within tissue at the target site angiosome,thereby promoting angiogenesis within the patient.
 2. The method ofclaim 1, wherein the ultrasonic energy has a frequency of between about0.5 MHz and about 5 MHz.
 3. The method of claim 1, wherein theultrasonic energy has a frequency of between about 1 MHz and about 3MHz.
 4. The method of claim 1, wherein the ultrasonic energy has a peaknegative pressure of between about 1 MPa and about 4 MPa.
 5. The methodof claim 1, comprising positioning the array of transducers above atleast two target site angiosomes, wherein the target site angiosomes areselected from the group consisting of: the medial calcaneal arteryangiosome; the medial plantar artery angiosome; the dorsalis pedisartery angiosome; the lateral calcaneal artery angiosome, and theanterior perforating branch artery angiosome.
 6. The method of claim 1,comprising positioning the array of transducers above each of thefollowing target site angiosomes: the medial calcaneal artery angiosome;the medial plantar artery angiosome; the dorsalis pedis arteryangiosome; the lateral calcaneal artery angiosome, and the anteriorperforating branch artery angiosome.
 7. The method of claim 1, furthercomprising measuring the reflected acoustic power of the ultrasonicenergy from at least one transducer of the array of transducers; anddiscontinuing directing the ultrasonic energy from the at least onetransducer found to have a reflected acoustic power above apredetermined threshold.
 8. The method of claim 1, further comprisingmeasuring the reflected acoustic power of the ultrasonic energy from atleast one transducer of the array of transducers; and discontinuingdirecting the ultrasonic energy from the at least one transducer foundto have a reflected acoustic power above a predetermined threshold. 9.The method of claim 1, further comprising measuring blood flow in realtime over the at least one angiosome, and adjusting parameters of theultrasonic energy based on the measured blood flow.
 10. The method ofclaim 1, wherein a surface area of the array of transducers covers atleast about 40% of a surface area of the entire wearable device.
 11. Themethod of claim 1, wherein a surface area of the array of transducerscovers at least about 60% of a surface area of the entire wearabledevice.
 12. The method of claim 1, wherein a surface area of the arrayof transducers covers at least about 80% of a surface area of the entirewearable device.
 13. A method of stimulating angiogenesis within apatient, comprising: providing a wearable non-invasive device comprisingat least one ultrasound transducer; positioning the at least oneultrasound transducer or an array of transducers proximate a skinsurface of a patient above a target site below the skin surface whereangiogenesis is desired; and causing a therapeutically effective amountof ultrasonic energy over a set time period to be directed toward thetarget site, thereby stimulating cavitation and shear stress withintissue at the target site, thereby promoting angiogenesis within thepatient.
 14. The method of claim 13, wherein the transducer comprises aTUS transducer.
 15. The method of claim 13, wherein the wearable deviceis applied continuously for at least 2 hours a day.
 16. The method ofclaim 13, wherein the wearable device is applied continuously for atleast 4 hours a day.
 17. The method of claim 13, wherein the wearabledevice is circumferentially wrapped around a portion of an extremity ofthe patient.
 18. The method of claim 13, wherein the wearable device isnon-circumferentially wrapped around a portion of an extremity of thepatient.
 19. The method of claim 18, wherein the extremity is a lowerextremity.
 20. The method of claim 19, wherein the skin surface is on atleast one of a thigh, a calf, an ankle, and a foot of a patient.
 21. Themethod of claim 13, for treating peripheral vascular disease.
 22. Themethod of claim 13, further comprising moving the device in acranio-caudal direction during use.
 23. The method of claim 13, furthercomprising rotating the device around a longitudinal axis of the deviceduring use.
 24. The method of claim 13, wherein positioning the at leastone ultrasound transducer proximate a skin surface comprises aligning apositioning guide on a sleeve of the device anteriorly or posteriorlywith respect to an extremity of the patient.
 25. The method of claim 13,wherein positioning the at least one ultrasound transducer proximate askin surface comprises positioning the at least one ultrasoundtransducer on the medial surface of the patient’s thigh.
 26. The methodof claim 13, wherein positioning the at least one ultrasound transducerproximate a skin surface comprises positioning the at least oneultrasound transducer on the posterior surface of the patient’s calf.27. The method of claim 13, wherein positioning the at least oneultrasound transducer proximate a skin surface comprises positioning theat least one ultrasound transducer on the anterior surface of thepatient’s ankle.
 28. The method of claim 13, wherein positioning the atleast one ultrasound transducer proximate a skin surface comprisespositioning the at least one ultrasound transducer on theinferior/plantar surface of the patient’s foot.
 29. The method of claim13, wherein positioning the at least one ultrasound transducer proximatea skin surface comprises positioning the at least one ultrasoundtransducer on the neck proximate the carotid artery.
 30. The method ofclaim 13, wherein positioning the at least one ultrasound transducerproximate a skin surface comprises positioning the at least oneultrasound transducer on the abdomen proximate the renal artery.
 31. Themethod of claim 13, wherein positioning further comprises moving the atleast one ultrasound transducer in an axial direction along the wearablenon-invasive device.
 32. The method of claim 13, wherein positioningfurther comprises rotating the at least one ultrasound transducer in aradial direction along the wearable non-invasive device.
 33. The methodof claim 13, further comprising measuring blood flow at the target site.34. The method of claim 33, further comprising adjusting the ultrasonicenergy based off the measured blood flow.
 35. The method of claim 13,further comprising sensing the temperature at the skin surface, anddecreasing or terminating the ultrasonic energy delivery if thetemperature is above a pre-determined level.
 36. The method of claim 13,wherein the wearable device is applied for at least 3 days a week, or atleast about 1 month.
 37. The method of claim 13, wherein the ultrasonicenergy is delivered below the sensation threshold of the patient. 38.The method of claim 13, wherein the transducer comprises solidpiezoelectric materials and a backing material.
 39. The method of claim38, wherein the transducer comprises a flexible surface to allow forconformal or flexible apposition to the skin surface of the patient. 40.The method of claim 13, further comprising assessing for the presence ofbone in a near-field via an imaging modality, and adjusting thepositioning of the transducer or a parameter of the ultrasonic energy ifbone is identified in the near-field.
 41. The method of claim 40,further comprising adjusting a parameter of the ultrasonic energy suchthat the target site is in a near-field, and bony structures of thepatient are in a far-field.
 42. The method of claim 13, furthercomprising recording data regarding a therapy session, and transmittingthe data to a remote device.
 43. The method of claim 13, furthercomprising activating a user interface to adjust a parameter regardingthe ultrasonic energy based on the comfort level of the patient.
 44. Themethod of claim 13, wherein the therapeutically effective amount ofultrasonic energy also stimulates vasodilation at the target site withinabout 24 hours of a therapy session, wherein the patient has acute limbischemia.
 45. The method of claim 13, for treating diabetic foot ulcers.46. The method of claim 13, for treating restless legs syndrome.
 47. Themethod of claim 13, wherein the target site is the gastrocnemius muscle.48. The method of claim 13, wherein the target site is the soleusmuscle.
 49. The method of claim 13, wherein the target site is theposterior tibial artery.
 50. The method of any of the preceding claims,wherein the target site is the femoral artery.
 51. The method of claim13, wherein the skin surface is over the plantar surface of the foot.52. The method of claim 13, wherein the target site is the plantar archarteries.
 53. The method of claim 13, comprising an array oftransducers, wherein each transducer in the array comprises a circularcross-section.
 54. The method of claim 13, comprising an array oftransducers, wherein each transducer in the array comprises an ovalcross-section.
 55. The method of claim 13, comprising an array oftransducers, wherein each transducer in the array comprises a sphericalcross-section.
 56. The method of claim 13, comprising an array oftransducers, wherein each transducer in the array comprises arectangular cross-section.
 57. The method of claim 13, comprising anarray of transducers, wherein each transducer in the array comprises arhomboid cross-section.
 58. The method of claim 13, comprising an arrayof transducers, wherein each transducer in the array comprises atrapezoidal cross-section.
 59. The method of claim 13, wherein a housingof the array of transducers comprises a trapezoidal cross-section. 60.The method of claim 13, wherein a housing of the array of transducerscomprises a rhomboid cross-section.
 61. The method of claim 13,comprising sensing reflected power back at the transducer or transducerarray in real time, and discontinuing the therapy if the reflected powersensed is greater than a predetermined value.
 62. The method of claim13, comprising a plurality of target sites, wherein the plurality oftarget sites is selected from the group consisting of: the medial thigh,posterior calf, anterior calf, dorsal midfoot, and plantar midfoot. 63.The method of claim 62, wherein the therapeutically effective amount ofultrasonic energy is directed to the plurality of target sitesconcurrently.
 64. The method of claim 62, wherein the therapeuticallyeffective amount of ultrasonic energy is directed to the plurality oftarget sites only one at a time.
 65. The method of claim 13, furthercomprising measuring perfusion at the target site in real time, andoutputting a parameter relating to perfusion onto a display.
 66. Themethod of claim 13, further comprising adjusting a parameter of theultrasonic energy after measuring perfusion at the target site.
 67. Themethod of claim 13, wherein the ultrasonic energy comprises a surfaceintensity:depth ratio of between about 0.10 W/cm³ and about 0.60 W/cm³.68. A system for stimulating angiogenesis within a patient, comprising:a wearable non-invasive device comprising an elastic sleeve comprisingat least one TUS transducer configured to be positioned proximate a skinsurface of a patient above a target site below the skin surface whereangiogenesis is desired; the ultrasound transducer configured to cause atherapeutically effective amount of ultrasonic energy over a set timeperiod to be directed toward the target site, thereby stimulatingcavitation and shear stress within tissue at the target site, therebypromoting angiogenesis within the patient at the target site; a portablepower supply operably attached to the sleeve; and an adhesive gel packpositionable between the at least one ultrasound transducer and theelastic sleeve.
 69. The system of claim 68, wherein the at least one TUStransducer is configured to deliver ultrasonic energy at a frequency ofbetween about 500 kHz and about 5 MHz.
 70. The system of claim 68,wherein the at least one TUS transducer is configured to deliverultrasonic energy at a PRF of between about 1 Hz and about 3 Hz.
 71. Thesystem of claim 68, wherein the at least one TUS transducer isconfigured to deliver ultrasonic energy at a pulse duration of betweenabout 1 ms and about 10 ms.
 72. The system of claim 68, wherein the atleast one TUS transducer is configured to deliver ultrasonic energy at aduty factor of between about 0.5% and about 2%.
 73. The system of claim68, wherein the at least one TUS transducer is configured to deliverultrasonic energy at a peak negative pressure of between about 1 MPa andabout 4 MPa.
 74. The system of claim 68, wherein the at least one TUStransducer is configured to deliver ultrasonic energy at a an acousticdose of between about 250-2000 mW/cm², and a derated Isppa of betweenabout 50-1000 W/cm².
 75. The system of claim 68, comprising an array ofTUS transducers.
 76. The system of claim 68, wherein the at least oneTUS transducer comprises solid piezoelectric materials and a backingmaterial.
 77. The system of claim 68, wherein the at least one TUStransducer comprises a flexible surface to allow for conformal orflexible apposition to the skin surface of the patient.
 78. The systemof claim 68, wherein the device comprises a sensor configured to assessfor the presence of bone in a near-field via an imaging modality, and acontroller configured to adjust the positioning of the transducer or aparameter of the ultrasonic energy if bone is identified in thenear-field.
 79. The system of claim 78, wherein the controller isfurther configured to adjust, based on data from the sensor, a parameterof the ultrasonic energy such that the target site is in a near-field,and bony structures of the patient are in a far-field.
 80. The system ofclaim 68, wherein the controller is configured to record data regardinga therapy session to a memory, and the device comprises a communicationsmodule to transmit the data to a remote device.
 81. The system of claim68, wherein the device comprises a control configured to adjust aparameter regarding the ultrasonic energy based on the comfort level ofthe patient.
 82. The system of claim 68, wherein the device is alsoconfigured to direct a therapeutically effective amount of ultrasonicenergy to stimulate vasodilation at the target site within about 24hours of a therapy session.
 83. The system of claim 68, comprising anarray of TUS transducers, wherein each transducer in the array comprisesa circular cross-section.
 84. The system of claim 68, comprising anarray of TUS transducers, wherein each transducer in the array comprisesan oval cross-section.
 85. The system of claim 68, comprising an arrayof TUS transducers, wherein each transducer in the array comprises aspherical cross-section.
 86. The system of claim 68, comprising an arrayof TUS transducers, wherein each transducer in the array comprises arectangular cross-section.
 87. The system of claim 68, comprising anarray of TUS transducers, wherein each transducer in the array comprisesa rhomboid cross-section.
 88. The system of claim 68, comprising anarray of TUS transducers, wherein each transducer in the array comprisesa trapezoidal cross-section.
 89. The system of claim 68, wherein ahousing of the array of transducers comprises a trapezoidalcross-section.
 90. The system of claim 68, wherein a housing of thearray of transducers comprises a rhomboid cross-section.
 91. The systemof claim 68, wherein the device comprises a power sensor configured tosense reflected power back at the one or more TUS transducers in realtime, and the device is configured to discontinue the therapy if thereflected power sensed by the power sensor is greater than apredetermined value.
 92. The system of claim 68, wherein the devicecomprises a thermocouple configured to measuring a temperature at theskin surface, and the device is configured to discontinue the therapy ifthe temperature is greater than a predetermined value.
 93. The system ofclaim 68, further comprising a perfusion-sensing element configured toassess perfusion at the target site, and output a parameter relating toperfusion onto a display.
 94. The system of claim 93, wherein the deviceis configured to modify a parameter of the ultrasonic energy aftermeasuring perfusion at the target site.
 95. A wearable system forstimulating angiogenesis within a patient, comprising: a wearablenon-invasive device comprising an elastic sleeve device comprising aproximal end and a distal end and comprising an array of TUS transducersconfigured to be positioned proximate a skin surface of a patient aboveat least one below-the-knee target site angiosome where angiogenesis isdesired; the array of ultrasound transducers configured to substantiallyconform to a calf, ankle, and foot of the patient, the array ofultrasound transducers further configured to cause a therapeuticallyeffective amount of ultrasonic energy over a set time period to bedirected toward the target site, thereby stimulating cavitation andshear stress within tissue at the target site, thereby promotingangiogenesis within the patient at the target site.
 96. The system ofclaim 95, wherein the distal end of the sleeve is a closed distal end.97. The system of claim 95, wherein the distal end of the sleeve is anopen distal end.
 98. The system of claim 95, wherein the system isconfigured to deliver ultrasonic energy having a surface intensity:depthratio of less than about 0.60 W/cm³.
 99. The system of claim 95, whereinthe ultrasonic energy has a frequency of between about 0.5 MHz and about5 MHz.
 100. The system of claim 95, wherein the ultrasonic energy has afrequency of between about 1 MHz and about 3 MHz.
 101. The system ofclaim 95, wherein the ultrasonic energy has a peak negative pressure ofbetween about 1 MPa and about 4 MPa.
 102. The system of claim 95,wherein a surface area of the array of transducers covers at least about40% of a surface area of the entire wearable device.
 103. The system ofclaim 95, wherein a surface area of the array of transducers covers atleast about 60% of a surface area of the entire wearable device. 104.The system of claim 95, wherein a surface area of the array oftransducers covers at least about 80% of a surface area of the entirewearable device.
 105. The system of claim 95, wherein at least sometransducers of the array of transducers are directly adjacent eachother.
 106. The system of claim 95, wherein at least some transducers ofthe array of transducers are spaced apart by no more than about 2 cmfrom each other.
 107. A system for stimulating angiogenesis within apatient, comprising: a wearable non-invasive device comprising anelastic sleeve comprising at least one TUS transducer configured to bepositioned proximate a skin surface of a patient above a target sitebelow the skin surface where angiogenesis is desired; the ultrasoundtransducer configured to cause a therapeutically effective amount ofultrasonic energy over a set time period to be directed toward thetarget site, thereby stimulating cavitation and shear stress withintissue at the target site, thereby promoting angiogenesis within thepatient at the target site; a portable power supply operably attached tothe sleeve; and an adhesive gel pack positionable between the at leastone ultrasound transducer and the elastic sleeve.
 108. The system ofclaim 107, wherein the at least one TUS transducer is configured todeliver ultrasonic energy at a frequency of between about 500 kHz andabout 5 MHz.
 109. The system of claims 107-108, wherein the at least oneTUS transducer is configured to deliver ultrasonic energy at a PRF ofbetween about 1 Hz and about 3 Hz.
 110. The system of claims 107-109,wherein the at least one TUS transducer is configured to deliverultrasonic energy at a pulse duration of between about 1 ms and about 10ms.
 111. The system of claims 107-110, wherein the at least one TUStransducer is configured to deliver ultrasonic energy at a duty factorof between about 0.5% and about 2%.
 112. The system of claims 107-111,wherein the at least one TUS transducer is configured to deliverultrasonic energy at a peak negative pressure of between about 1 MPa andabout 4 MPa.
 113. The system of claims 107-112, wherein the at least oneTUS transducer is configured to deliver ultrasonic energy at a anacoustic dose of between about 250-2000 mW/cm², and a derated Isppa ofbetween about 50-1000 W/cm².
 114. The system of claims 107-113,comprising an array of TUS transducers.
 115. The system of claims107-114, wherein the at least one TUS transducer comprises solidpiezoelectric materials and a backing material.
 116. The system ofclaims 107-115, wherein the at least one TUS transducer comprises aflexible surface to allow for conformal or flexible apposition to theskin surface of the patient.
 117. The system of claims 107-116, whereinthe device comprises a sensor configured to assess for the presence ofbone in a near-field via an imaging modality, and a controllerconfigured to adjust the positioning of the transducer or a parameter ofthe ultrasonic energy if bone is identified in the near-field.
 118. Thesystem of claim 117, wherein the controller is further configured toadjust, based on data from the sensor, a parameter of the ultrasonicenergy such that the target site is in a near-field, and bony structuresof the patient are in a far-field.
 119. The system of claims 107-118,wherein the controller is configured to record data regarding a therapysession to a memory, and the device comprises a communications module totransmit the data to a remote device.
 120. The system of claims 107-119,wherein the device comprises a control configured to adjust a parameterregarding the ultrasonic energy based on the comfort level of thepatient.
 121. The system of claims 107-120, wherein the device is alsoconfigured to direct a therapeutically effective amount of ultrasonicenergy to stimulate vasodilation at the target site within about 24hours of a therapy session.
 122. The system of claims 107-121,comprising an array of TUS transducers, wherein each transducer in thearray comprises a circular cross-section.
 123. The system of claims107-122, comprising an array of TUS transducers, wherein each transducerin the array comprises an oval cross-section.
 124. The system of claims107-123, comprising an array of TUS transducers, wherein each transducerin the array comprises a spherical cross-section.
 125. The system ofclaims 107-124, comprising an array of TUS transducers, wherein eachtransducer in the array comprises a rectangular cross-section.
 126. Thesystem of claims 107-125, comprising an array of TUS transducers,wherein each transducer in the array comprises a rhomboid cross-section.127. The system of claims 107-126, comprising an array of TUStransducers, wherein each transducer in the array comprises atrapezoidal cross-section.
 128. The system of claims 107-127, wherein ahousing of the array of transducers comprises a trapezoidalcross-section.
 129. The system of claims 107-128, wherein a housing ofthe array of transducers comprises a rhomboid cross-section.
 130. Thesystem of claims 107-129, wherein the device comprises a power sensorconfigured to sense reflected power back at the one or more TUStransducers in real time, and the device is configured to discontinuethe therapy if the reflected power sensed by the power sensor is greaterthan a predetermined value.
 131. The system of claims 107-130, whereinthe device comprises a thermocouple configured to measuring atemperature at the skin surface, and the device is configured todiscontinue the therapy if the temperature is greater than apredetermined value.
 132. The system of claims 107-131, furthercomprising a perfusion-sensing element configured to assess perfusion atthe target site, and output a parameter relating to perfusion onto adisplay.
 133. The system of claim 132, wherein the device is configuredto modify a parameter of the ultrasonic energy after measuring perfusionat the target site.
 134. A wearable system for stimulating angiogenesiswithin a patient, comprising: a wearable non-invasive device comprisingan elastic sleeve device comprising a proximal end and a distal end andcomprising an array of TUS transducers configured to be positionedproximate a skin surface of a patient above at least one below-the-kneetarget site angiosome where angiogenesis is desired; the array ofultrasound transducers configured to substantially conform to a calf,ankle, and foot of the patient, the array of ultrasound transducersfurther configured to cause a therapeutically effective amount ofultrasonic energy over a set time period to be directed toward thetarget site, thereby stimulating cavitation and shear stress withintissue at the target site, thereby promoting angiogenesis within thepatient at the target site.
 135. The system of claim 134, wherein thedistal end of the sleeve is a closed distal end.
 136. The system ofclaim 134, wherein the distal end of the sleeve is an open distal end.137. The system of claims 134-136, wherein the system is configured todeliver ultrasonic energy having a surface intensity:depth ratio of lessthan about 0.60 W/cm³.
 138. The system of claims 134-137, wherein theultrasonic energy has a frequency of between about 0.5 MHz and about 5MHz.
 139. The system of claims 134-138, wherein the ultrasonic energyhas a frequency of between about 1 MHz and about 3 MHz.
 140. The systemof claims 134-139, wherein the ultrasonic energy has a peak negativepressure of between about 1 MPa and about 4 MPa.
 141. The system ofclaims 134-140, wherein a surface area of the array of transducerscovers at least about 40% of a surface area of the entire wearabledevice.
 142. The system of claims 134-141, wherein a surface area of thearray of transducers covers at least about 60% of a surface area of theentire wearable device.
 143. The system of claims 134-142, wherein asurface area of the array of transducers covers at least about 80% of asurface area of the entire wearable device.
 144. The system of claims134-143, wherein at least some transducers of the array of transducersare directly adjacent each other.
 145. The system of claims 134-144,wherein at least some transducers of the array of transducers are spacedapart by no more than about 2 cm from each other.